Respiratory Toxicants Lecture 1, Spring 2025

Respiratory toxicants Respiratory toxicants: Overview Sources Acute Bovine Pulmonary Edema & Emphysema (ABPE)  ABPE Sources Herbicide ‘Perilla’ or ‘purple’ Mint Paraquat (Perilla frutescens) Feed Lush past...

Respiratory toxicants Respiratory toxicants: Overview Sources Acute Bovine Pulmonary Edema & Emphysema (ABPE)  ABPE Sources Herbicide ‘Perilla’ or ‘purple’ Mint Paraquat (Perilla frutescens) Feed Lush pastures Moldy sweet potato Peanut vine hay Soybeans Toxic plant Perilla mint plant  ABPE General Mechanism Paraquat 10x affinity for alveolar cells Toxicant or metabolite PQ: reduction/oxidation cycling type 1 alveolar cells  endothelial cells hydrogen peroxide superoxide anion hydroxyl radical ROS reactive intermediates  CELL DEATH  ABPE Lush pastures Perilla mint Moldy sweet potato L-tryptophan Fusarium spp Perilla ketone rumen plant 3-methyl indole 4-ipomeanol lung lung lung Reactive Intermediates  ABPE Clinical syndrome Treatment Paraquat No specific antidote Initial GI distress Remove source Supportive: fluid Acute respiratory distress diuresis Cyanosis, severe dyspnea, frothing Activated charcoal Limited success Lesions: Clay-based adsorbents Pulmonary edema, for PQ (Novasil Plus) emphysema, fibrosis. Effective, but not widely Paraquat: necrosis of adopted (can be used as proximal tubule cells an additive for prevention) Respiratory toxicants Cyanogenic glycoside plants Cyanogenic glycoside-containing plants Black cherry, Choke cherry (Prunus spp) Hydrangeas (Hydrangea spp) Flowering quince (Chaenomales spp) Crabapple (Malus spp) Johnson grass & other Sorghum spp. Common vetch (Vicia sativa) Major cyanogenic glycosides: amygdalin, prunasin, dhurrin, linamarin Cyanogenic glycoside-containing plants Black Cherry Choke Cherry Cyanogenic glycoside-containing plants Hydrangeas Oakleaf hydrangea Cyanogenic glycoside-containing plants Flowering Quince Cyanogenic glycoside-containing plants Crabapple Cyanogenic glycoside-containing plants Johnson grass Cyanogenic glycoside-containing plants Common vetch  Cyanogenic glycosides Conditions favoring intoxication: Cyanogenic glycosides are found in all parts of the plants (highest in seeds, young growing plant) Enzymes (e.g. β-glucosidase) in the plant convert the glycosides to hydrogen cyanide (HCN) during chewing or stress (e.g. frost) This conversion can also occur in the rumen, making ruminants the most susceptible species CN- is absorbed across the gut and rapidly distributes in the blood  Cyanogenic glycosides Mechanism of action CN- forms stable complex with Fe3+ of cytochrome oxidase (complex IV of the ETC) Prevents conversion of Fe3+ to Fe2+ Inhibits electron transport, cellular respiration Blood is oxygenated (cherry red) but O2 cannot be utilized by tissues Cyanogenic glycosides Clinical syndromes Death within a few minutes Death within 20-120 minutes (dose- dependent) Animals surviving beyond 120 minutes will usually recover  Cyanogenic glycosides Clinical signs Initial Salivation (‘frothing at the mouth’) and rapid breathing Progression Marked dyspnea, weakness, muscle fasciculation, urination, defecation, Staggering, tachycardia, mydriasis Terminal Lateral recumbency, convulsions, cyanosis Death from respiratory paralysis  Cyanogenic glycosides Treatment Remove from source Goal (mostly small animals): forming a decoy receptor Hydroxycobalamin (Vit B12a; iv), forms cyanocobalamin; excreted in the urine Goal (large and small animals): Split the CN— Fe3+ bond and excrete CN Amyl and/or Sodium nitrite (inhlation/iv) Forms MetHb which can then bind CN to form cyanoMetHb Cytochrome oxidase is reactivated Sodium thiosulfate Thiol reacts with CN from cyanoMetHb to form hydrogen thiocyanate Thiocyanate is excreted in urine Respiratory toxicants One health perspective  One health perspective Pets and humans share indoor and outdoor environments Wildlife habitat overlaps increasingly with humans too Example: 2025 LA wild fires Contaminated air: mix of particulate matter, CO, NOx, Pb, chlorine, PAHs, plus many others Short- and long-term effects PM 2.5 is a particular concern Sled dogs in Alaska wildfire study (2021) Food for thought : Think of factors that make the respiratory tract major target of toxicants… Cardiovascular and Blood System Toxicants Anticoagulant Toxicants Rodenticides Aspirin  Anticoagulant rodenticides Hemorrhagic syndrome 1920s Sweet clover hay & silage Fungal metabolite: Coumarin 4-hydroxycourmarin (Dicumarol) Anticoagulant activity Synthetic dicumarol analog 1940s WARFARIN (Wisconsin Alumni Research Foundation)  Anticoagulant rodenticides Bait blocks, grain mixes, tracking powders  Anticoagulant rodenticides 1st ‘Generation’ 2nd ‘Generation’ 1940s 1970s Low potency Higher potency multiple doses single dose aversion retained longer rapid excretion *relay toxicosis Products: Products: Brodifacoum (t½: 120 d) Warfarin (t½: 14.5 h) Bromadiolone Dicoumarol Diphacinone Pindone All mammals and birds; dogs and cats most common Anticoagulant rodenticides Vitamin K-like Lipid soluble vitamin Required for activation of clotting factors Warfarin Antagonize Vit K Brodifacoum Brodifacoum Vitamin K-dependent factors II Anticoagulant rodenticides: Mechanism of action Vit K epoxide reductase Vit. K dependent clotting factors: II, VII, IX, X, protein C prothrombin  thrombin fibrinogen  fibrin  Anticoagulant rodenticides Toxicokinetics Absorption Slow, but complete - 90% Peak plasma levels - 12 hrs Distribution Plasma - protein bound Cross the placenta Retained in the liver Elimination CytoP450 oxidases Excreted in urine Brodifacoum – bile, enterohepatic recycling  Anticoagulant rodenticides Toxicosis Delayed onset Clinical signs not evident until activated factors used up (2-3 d) Death - Cerebral, thoracic, pericardial hemorrhage 2nd generation compounds!  Anticoagulant rodenticides Early Subcutaneous hematomas, epistaxis, bleeding gums, dark tarry stools, bloody vomit Late Dyspnea, pale mucous membranes, exercise intolerance Anorexia, weakness, ataxia Widespread spontaneous hemorrhaging swelling of joints, submandibular edema  OSU Veterinary Teaching Hospital Clinical signs Percent Dyspnea 57 Lethargy 48 Coughing/hemoptysis 30 Palor 26 Prolonged ACT 100 Prolonged PT 100 Prolonged PTT 100 Anemia 83 Thrombocytopenia 61 Hypoproteinemia 57 83% survival with appropriate care!  Anticoagulant rodenticides Labs Hematology PT: 2-6x longer; early indicator (VII, extrinsic) May be useful in asymptomatic animals Activated PTT: 2-4x longer Activated Coagulation Time: 2-10x longer Least sensitive; 3 days post-ingestion; symptomatic PIVKA (proteins induced in Vit K absence/antagonism) Potentially more specific for anticoagulants Anemia; possible thrombocytopenia  Anticoagulant rodenticides Treatment Known exposure, asymptomatic GI decontamination PT time baseline Antidote: Vitamin K1 Oral form Send home with oral form; give daily with food Repeat PT (2-3 days) IV: anaphylaxis, hemolysis, Heinz body anemia IM: hematoma  Anticoagulant rodenticides Symptomatic animal Stabilize: whole blood or plasma transfusion Dyspneic: thoracentesis GI decontamination: limited value Blood draw for clotting times Vitamin K1 therapy – SC route 12 hrs: (repeat PT); oral form, fatty meal Handle carefully, keep warm, stress-free Limit physical activity Daily PT times  Anticoagulant rodenticides Stabilized Contraindications Send home on oral Vit. K1 therapy Broad spectrum antibiotics Decrease Vit. K Duration absorption Depends on agent Warfarin compounds: 14 d Sulfonamides, Brodifacoum, corticosteroids Diphacinone - 30 d Displace toxicant from Weekly PT values plasma proteins After treatment ends: 5 to 7 days follow up PT Aspirin (NSAIDs)  Aspirin Salicylate Therapeutic Original NSAID Cat: 10-25 mg/kg/day to 81, 325, 500 mg tabs EOD Alka-Seltzer, arthritis Dog: 25-35 mg/kg TID creams PeptoBismol, Kaopectate Toxic Canine formulations Cat: 80-120 mg/kg daily Pet stores 10-12 days 100, 325 mg Dog (acute): 500 mg/kg BID Dog (chronic): 100-300 mg/kg/day for 1-4 weeks; 50 mg/kg for 8 weeks  Aspirin Toxicokinetics Mechanism Inhibit COX-1 and COX-2 Absorption enzymes Weak acid Irreversibly acetylates platelet Biotransformation COX Glycine or glucuronic acid conjugation Cats: increased T ½ Renal excretion Blocks platelet aggregation Reduces gastric and renal blood flow. Reduces gastric mucus. Increases gastric H+ secretion. High doses: uncouples oxidative phosphorylation.  Aspirin Toxicosis Labs Lower doses Anemia Gastroenteritis Cat: Heinz body anemia Nausea, vomiting, Prolonged clotting times GI bleeding Decreased renal function Higher doses Elevated respiration Depression, lethargy Dehydration Hyperthermia  Aspirin Treatment Stabilize Blood transfusion Fluids (sodium bicarbonate) Decontamination Emesis (recent exposure) Activated charcoal & cathartic Urine alkalinization GI protectants Misoprostol (Cytotec)- synthetic PG Sucralfate H2 antagonists Monitor renal function and PCV