Respiratory Toxicants and ABPE

Respiratory Toxicants

• Respiratory toxicants can originate from various sources, including air pollution, poor ventilation, food/feed/water, volatile compounds, mycotoxins, plants, pesticides, drugs, and many others.
• Exposure to respiratory toxicants can lead to various effects on the respiratory system, including asphyxiation, irritation, pulmonary edema, epithelial necrosis, emphysema, fibrosis, and more.
• Specific examples of respiratory toxicants mentioned include carbon monoxide, fluorocarbons, heavy metals, nitrogen oxides, smog, smoke, ammonia, carbon dioxide, carbon monoxide, hydrogen sulfide, methane, chlorine, formaldehyde, and more.
• Mycotoxins, ipomeanol, hydrocarbions fuels and solvents (paints and Teflon), Astragalus and Brassica (rape), 3-methyl indole, paraquat, ANTU, organophosphates, endotoxins (contaminants), and organic iodide were also listed as potential respiratory toxicants.

Acute Bovine Pulmonary Edema & Emphysema (ABPE)

• ABPE is a respiratory condition.
• Sources of ABPE include herbicides (like paraquat), lush pastures, moldy sweet potatoes, peanut vine hay, and soybeans. Additionally, the perilla mint plant is listed as a toxic plant that can cause ABPE.
• The general mechanism of ABPE involves the toxicant, or a metabolite of it, affecting type 1 alveolar cells and endothelial cells, generating reactive oxygen species (ROS). This, in turn, leads to cell death.
• Paraquat has a 10x affinity for alveolar cells, undergoing reduction/oxidation cycles, and produces hydrogen peroxide, superoxide anion, and hydroxyl radical; all agents that lead to cell death.
• Exposure to plants like perilla mint, moldy sweet potatoes and lush pastures, can result in the production of L-tryptophan, which is metabolized into 3-methyl indole in the rumen. These are then transported to the lungs and contribute to the development of reactive intermediates, leading to ABPE.

Cyanogenic Glycoside-Containing Plants

• Cyanogenic glycosides are present in various plants.
• Toxic plants include black cherry, choke cherry, hydrangeas, flowering quince, crabapple, Johnson grass (and other Sorghum spp.), common vetch.
• Cyanogenic glycosides, especially in these plants, transform into hydrogen cyanide (HCN) during consumption or when the plant experiences stress factors like frost.
• The transformation of glycosides into HCN occurs in the rumen of ruminants, therefore making ruminants more susceptible.
• HCN is rapidly absorbed throughout the gut and dispersed throughout the bloodstream.

Cyanogenic Glycosides: Mechanism of Action

• Cyanide (CN−) forms a stable complex with iron (Fe3+) in cytochrome oxidase, a critical component of the electron transport chain (ETC).
• This complex formation prevents the conversion of Fe3+ to Fe2+
• Disruption of this process inhibits electron transport and cellular respiration.
• The body can still look oxygenated (appear cherry red) but cells can't use the oxygen for metabolism.

Cyanogenic Glycosides: Clinical Syndromes

• Death can happen after only minutes in some cases of cyanide poisoning or can be dependent on the dose.
• Animals that survive beyond 120-minute exposure to cyanide commonly recovered.
• Initial clinical signs encompass salivation, rapid breathing, marked dyspnea, weakness, muscle fasciculation, urination, defecation and staggering, tachycardia and mydriasis.
• Terminal signs include lateral recumbency, convulsions, and cyanosis accompanied by death due to respiratory paralysis.

Cyanogenic Glycosides: Treatment

• Removal of the source or the food causing the poisoning is crucial.
• Treatment differs depending on the size of the animal.
• For small animals, the goal is forming a decoy receptor, utilizing hydroxycobalamine as a treatment method, and allowing body to eliminate in urine.
• Larger animals treatment involves using amyl and/or sodium nitrite to split CN-Fe3+ bond for elimination of cyanide from the system.

One Health Perspective

• Pets and humans share environments making them vulnerable to exposure of same toxins such as the contaminated air from LA wildfire study (2025), with examples of CO, NOx, Pb, chlorine, PAHs, and PM 2.5.
• Sled dogs in Alaska wildfire study (2021) experienced adverse effects of particulate matter due to similar environmental factors.

Cardiovascular and Blood System Toxicants: Anticoagulant Rodenticides

• Anticoagulant rodenticides are toxic substances aimed to kill rodents.
• Examples include rodenticides and aspirin.
• Hemorrhagic syndrome is an effect that can occur after exposure to rodenticides like sweet clover hay and silage.
• Some rodenticides are fungal metabolites like coumarin, 4-hydroxycourmarin (Dicumarol). Other examples include synthetic dicumarol analogs, such as Warfarin.
• Rodenticides come in different forms such as bait blocks, grain mixes, and tracking powders.

Anticoagulant Rodenticides: 1st/2nd Generation

• First-generation rodenticides (1940s) feature low potency, multiple doses, and the potential for aversion.
• Rodenticides are rapidly excreted.
• Second-generation rodenticides (1970s) showcase higher potency, single doses, potentially longer retention, and the risk of "relay toxicosis."
• Warfarin, Dicoumarol, and Pindone fall under first generation rodenticides, while Brodifacoum, Bromadiolone, and Diphacinone belong to the second generation.

Anticoagulant Rodenticides: Vitamin K

• Vitamin K is a lipid-soluble vitamin vital for activation of clotting factors.
• Anticoagulant rodenticides antagonize vitamin K, impacting blood coagulation.
• Toxicity from rodenticides can cause delayed onset; clinical signs may not become evident until clotting factors are used up.
• Examples of clinical effects due to rodenticides include cerebral, thoracic, and pericardial hemorrhage, and swelling of joints accompanied by edema.

Anticoagulant Rodenticides: Toxicokinetics

• Rodenticide absorption is slow but complete (approximately 90%).
• Peak plasma levels usually occur within 12 hours after exposure.
• Rodenticide distribution involves binding to plasma proteins and retention within the liver.
• Elimination involves metabolism by cytochrome P450 oxidases and excretion in the urine.

Anticoagulant Rodenticides: Clinical signs and labs

• Clinical signs of rodenticides exposure include cutaneous hematomas, epistaxis, dark tarry stools, and bloody vomit, dyspnea, paleness of mucous membranes, exercise intolerance, anorexia, weakness, ataxia, spontaneous hemorrhaging, and swelling of joints
• Labs that are useful in diagnosis include PT (2-6x longer), activated PTT, activated coagulation time (2-10x longer). These tests assess clotting times and can help detect if excessive clotting factors are being used up from a poisoning event.
• PIVKA (proteins induced in Vitamin K absence/antagonism) tests can aid diagnosis in a more specific manner.

Anticoagulant Rodenticides: Treatment

• For asymptomatic animals, GI decontamination, PT baseline measurement, and oral vitamin K treatment are often sufficient.
• For symptomatic animals, whole blood or plasma transfusion is indicated to improve health.
• In cases of dyspnea, thoracentesis may be performed.
• Vitamin K₁ therapy may be administered subcutaneously.

Anticoagulant Rodenticides: Stabilization and Duration

• Stabilize symptomatic animals with appropriate treatment to meet their needs.
• Duration of treatment depends on the specific rodenticide and can range from 14 days for warfarin to 30 days for Brodifacoum and Diphacinone.
• Routine PT(prothrombin time) values are taken weekly until it returns back to normal levels.

Anticoagulant Rodenticides: Contraindications

• Wide spectrum antibiotics, decrease Vitamin K absorption from sulfonamides and corticosteroids need to be monitored and avoided or taken with extra caution when treating.

Aspirin (NSAIDs)

• Aspirin is a salicylate and NSAID (non-steroidal anti-inflammatory drug).
• Original aspirin is available as 81, 325, and 500 mg tablets.
• Other products containing aspirin include Alka-Seltzer and arthritis creams.
• Aspirin is also found in Pepto-Bismol, Kaopectate, and canine formulations.
• Aspirin is frequently present in pet stores in 100 and 325 mg forms.
• Typical therapeutic dosage for cats to dogs ranges from 10-25 mg/kg/day to 25-35 mg/kg/day, respectively.
• Aspirin toxicity in cats and dogs typically range from 80-120 mg/kg, taken for extended periods of 10 to 12 days.

Aspirin: Toxicokinetics

• Aspirin is absorbed via passive diffusion from the stomach and intestines.
• Biotransformation of aspirin occurs primarily via acetylation of enzyme COX-1 and COX-2 to prevent the formation of prostaglandins or the formation of thromboxanes.
• Excretion primarily occurs via renal pathways.
• Cats can exhibit increased half-life compared to other species.

Aspirin: Toxicosis

• Symptoms of lower-dose aspirin toxicity include gastroenteritis, nausea, vomiting, and GI bleeding, while moderate to high doses will induce vomiting, elevated respiration, depression, lethargy, dehydration, and/or hyperthermia.
• Diagnosis can be performed using lab tests like blood tests.

Aspirin: Treatment

• Treatment for aspirin toxicity involves stabilizing the patient, providing blood transfusions, fluids (such as sodium bicarbonate), decontamination (using emesis, activated charcoal or cathartic), urine alkalinization, and GI protectants.