Pesticide toxicity (Proceedings)

Pesticides - Agents (physical, chemical or biological) designed to kill pests that interfere with the comfort, health or economic wellbeing of man. Accompanying their beneficial effects, illnesses and deaths in man and animal alike, have been reported. Recorded use of compounds in the control of pests goes back to 1000 BC, when sulfur was used for such purpose. Since then their have been continued development of more effective and safe pesticides. Currently in use today are > 600 pesticides, constituting 15,000 compounds in 3,500 formulations.

In this presentation, pesticides will be discussed as a group (Rodenticide, Insecticides) on the basis of the syndrome (acute and/or chronic), mode of action, toxicity, toxicokinetics, clinical signs, diagnosis, treatment and prognosis. Newer insecticides (Fipronil, imidacloprid, Serlamectin, Lufenuron, nitenpyram, their vehicles, and petroleum distillates) will be addressed as to their efficacy and low toxicity. When possible (time allowing) cases scenarios will be included.

Pesticides Classified by groups are Insecticides (the most common cause of small animal Poisonings), Herbicides, Fungicides, Rodenticides, and Neonicotinoids. Classified on the basis of production: Herbicides > Insecticides > Fungicides > Rodenticides > others.

Rodenticides (anticoaguants (warfarin and second generation compounds) cholecalciferol, Bbomethalin, (strychnine, 1080, thallium, ANTU, zinc phosphide not currently widely used, to name a few) are the most common causes of animal poisoning, the majority attributable to anticoagulant baits. The relative incidence rates: Dogs > Cats

Common clinical signs (present [+] or absent [-]) associated with rodenticide poisoning in companion animals

They share common mechanism of action and are classified as first or second generation, indicating their potency and ability to kill warfarin resistant rodents

Toxicity of Common Anticoagulant Rodenticides

Toxicokinetics

They are 90% absorbed from the GI tract; 95% plasma protein bound; undergo Liver metabolism; and Renal excretion; Plasma T1/2 of 20-24h (dogs) – first generation; Plasma T1/2 of 6 ± 4 days – second generation

Toxicity

All animals including birds are susceptible. Concurrent administration of other compounds (aspirin, phenylbutazone) which are also highly protein bound, increase tocicity. Relay toxicity – moderate to high with second generation anticoagulants.

Mechanism of action

Interfere with the enzyme vitamin K reductase which is essential for the re-conversion of inactive vitamin K to its Active Quinone form. This leads to a decrease in vitamin K-dependent clotting factors (11, V11, 1X, and X). Vitamin K – Cofactor in clotting factors activation

Deficiency – Inhibition of vitamin K epoxide reductase

Clinical sign– Delayed 2 to 3 days post ingestion. Severity and duration – depend on dose and species of anticoagulant ingested

Slows extrinsic/intrinsic and common clotting pathways

Depression, vomiting, weakness, anorexia, diarrhea, dyspnea, hemorrhage, melena, epistaxis, sudden deaths in animal bleeding into – thorax, pericardium, mediastinum, abdomen (untreated animals) and Hypovolemic shock

Diagnosis Based on- History of exposure – difficult in most cases; appropriate clinical signs;

Laboratory confirmation (stomach contents, liver, un-clotted blood (preferred specimen), or

kidneys, and positive response to vitamin K therapy is supportive

Clinical Pathology – helpful supportive data

Decreased PCV (anemia, Prolong bleeding at injection sites, Delayed clotting - whole blood

Increased activated clotting time (2 – 10 folds), Prolong activated prothrombin time (PT): 2-6 folds, Increased on stage prothrombin time (OSPT) and activated partial prothrombin time (APTT) by 2-4 folds

Platelets - normal to marginally low, Fiber degeneration products – normal, Elevated carboxylated forms of vitamin K – dependent coagulation factor (PIVKA)

First generation – persist for 14 days; Second generation – Persist for > 30 days

Treatment

Vitamin K1 (Phytonadione) therapy (PO preferred) effective in 6-12h

Treatment Guidelines - First generation – Vitamin K1 therapy for 14 days (adequate).

Second generation – Vitamin K1 therapy for at least 30 days

Vitamin K3 is contraindicated - Stores poorly, requires metabolic activation, and can cause anemia

Bromethalin

Introduced mid 1980s

Trade names – vengeance, Assault, Trounce

Chemical name

N-methyl-2,4-dinitro-N(2, 4, 6-tribromophenyl)-6-(fluoromethyl)-benzenamine

Toxicity (estimated LD50)

Dogs – 4.7 mg/kg

Cats – 1.8 mg/kg

Toxicokinetics

     • Rapid absorption from GI tract

     • Peak plasma concentration reached 4h post ingestion and has a plasma T1/2 of 5-6 days

     • Liver metabolism (N-demethylation), forming toxic metabolite (Des-methylbromethalin)

     • Via hepatic P450s

     • Biliary excretion (Slow due to enterohepatic recirculation)

Mechanism of action

Desmethylbromethalin enhanced lipid peroxidation causing myelin injury

Afffects mitochondria - Uncouples oxidative phosphorylation, causing a lack of adequate ATP (energy) >> altered ionic homeostasis >> myelin injury. Sodium/Potassium ion channel pumps are energy dependent, therefore a lack of energy results in cerebral edema

Clinical signs

Toxic dose ingested – 24h delay in the appearance of clinical signs

Acute syndrome

Severe muscle tremor, Hyperthermia, Extreme hyperexcitablity, Focal motor and generalized seizures

Less than an acute toxic dose ingested – 24 to 36h delay in the appearance of clinical signs

Diagnosis

     • Exposure history

     • White matter edema (similar to trialkyl tins, hexachlorophene)

     • Clinical signs within certain time following exposure

     • Chemical confirmation – not commonly done therefore of questionable clinical significance

     • Detect bromethalin/metabolites in fat, brain, liver

Treatment

     • Prevent further absorption – emetic, repeated activated charcoal administration, saline or osmotic cathartic. Control cerebral edema - Dexamethasone and osmotic diuretic (Mannitol, Furosemide) are reported helpful

Cholecalcifrol

     • Quintox, Rampge, ortho Rat-B-Gone, Ortho, Mouse-B-Gone

     • Bait (0.075% cholecalciferol), Calcipotrol – anti-psoriasis cream. Access to dogs (vitamin D source)

Toxicity

     • LD50 for pure technical material – 88mg/kg

     • Toxicosis (dogs) – bait estimated to be 1gram bait/# body weight (equivalent to 2mg

     • cholecalciferol/kg body weight = 80,000 U/kg body weight

     • Animals with pre-existing kidney disease may be predisposed to toxicity.

Metabolism

     • Cholecaciferol (fat soluble) is absorbs via the lymphatic system

     • Liver metabolism to 25-hydroxycholecalciferol (major circulating metabolite)

     • Kidney metabolism to 1,25-dihydrocholecalciferol (calcitrol) – active

     • Bone re-sorption, Intestinal calcium transport

     • Parent compound and 25-hyroxycholecalciferol (limited bio.activity)

Mechanism of action

     • Vitamin D intestinal absorption from GI tract

     • Vitamin D metabolism in Liver and kidney

     • Vitamin D metabolites to GI tract and bone >> increased calcium absorption (GI tract), increased calcium mobilization (bone)

     • Hypercalcemia and hyperphosphatemia >> dystrophic calcification (Kodney)

     • Increases intestinal calcium absorption

     • Stimulates bone re-sorption

     • Increases tubular re-absorption of calcium and phosphorus

Clinical signs: 12-36h post ingestion

Related hypercalcemia development - Vomiting, Depression, Anorexia, Polydipsia, Diarrhea, Pulmonary and GI hemorrhage

Dystrophic calcification, Clinical Pathology

Hypercalcemia (Serum Ca > 12mg/dl) and dystrophic calcifiction

Hyperphosphatemia, hyperproteinemia and azotemia

Low urine specific gravity (1.001-1.007), glucosuria and sediments (leukocytes, RBC and cast)

Metabolic acidosis

Pathology

Dogs – Diffused hemorrhage (gastric mucosa, duodenum and jejunum)

Mineralization – myocardium, arterial membranes, glomerular capillary walls, renal cortical tubular basement, membranes, bowman's capsules and stomach

Hypercalcemia (> 11 mg/dl); Hyperphosphatemia develops within 24-36 hours

Clinical Pathology

     • Azotemia

     • Hyperproteinemia

     • Proteinuria

     • Glycosuria

     • Hyposthenuria

     • Urine specific gravity = 1.002 - 1.006

     • Elevated serum levels of 25-hydroxy and 1,25-dihydroxy cholecalciferol

Diagnosis

History of exposure, appropriate clinical signs, Hypercalcemia, hyperphosphatemia (develop within 12-24h, post cholecalciferol ingestion

Soft tissue mineralization, Increased serum cholecalciferol/metabolites.25-hydroxy., 24,25-dihydroxy., 125-dihydroxy. Increased total kidney calcium

Treatment

GI detoxification (emetic, activated charcoal, saline or osmotic cathartic)

Correct electrolyte imbalance

Therapy aimed at reducing serum calcium (hyercalcemia)

     • Calciuresis (IV 0.9% physio. Saline)

     • Diuretic (Furosemide 2-5 mg. q8-12h)

     • Oral Prednisone 2mg/kg q12h

     • Solmon calcitonin (sq. 4-6 IU/kg q2-3h)

Continue treatment until serum calcium stabilizes. Control arrhythmias and rare seizures

Determine serum calcium levels and BUN daily for the first three days post exposure, In symptomatic animals with existing hypercalcemia, continue diuresis (Cholecalciferol-induced hypercalcemia persist for several weeks) – long term management of these cases

Continued case management – maintenance

     Furosemide (2-4.5mg/kg orally q8-12h)

     Prednisone (2mg/kg orally q12h)

Calcitonin

Ineffective when administered alone

T1/2 is short (3-4h) therefore multiple doses over treatment period (2-3 weeks)

Adverse reaction (vomiting and anorexia) to long term treatment

Pamidronate and Clodronate, drugs used as bone re-sorption inhibitors in man have been reported to be helpful in dogs: Decreased serum calcium and improved renal function when compared to saline alone