Toxicology Exam 1

maximum tolerable Mo in diet

5-10 ppm and the Cu:Mo dietary ratio should be 6:1

contrac

2nd generation rodenticide

follow up for rodenticide toxicity

Check clotting times for 1 week after termination of therapy

signalment/history of metaldehyde toxicity

Dogs at greatest risk Risk factors o None in particular Historical findings o Signs and observations often reported by the owner Interactions with Drugs, Nutrients, or Environment o Drugs that use the cP450 enzymes for metabolism are protective from toxicity

prognosis for vitamin D/cholecalciferol toxicity

Guarded unless caught early before extensive tissue mineralization has occurred

metaldehyde supportive therapy

Maintain hydration: lactated ringers (40-90 mg/kg/hr); For Acidosis (if pH < 7.2): Na Bicarb mEq = 0.3 X BW(kg) X (desired - observed plasma HCO3- ) Control hyperthermia Sequel - liver damage, blindness (transient) Prognosis is dosage dependent, improved by early therapy

toxicity doses of metaldehyde

Oral LD50 in dogs...(210 - 600) mg/kg bw Oral LD50 in cats...207 mg/kg bw Lethal dosage for cattle 200 mg/kg Lethal dosage for horses 60 - 100 mg/kg Ducks & chickens MLD 300 & 500 mg/kg Lower doses can cause signs - a few pellets can produce signs in small puppies Unlikely to cause relay poisoning

prevention of bromethalin toxicity

Owner education and proper baiting techniques

prevention of metaldehyde toxicity

Owner education and proper baiting techniques

prognosis-bromethalin toxicity

Usually poor unless diagnosed and decontaminated very early

examples of toxicology

-accidental access to poisons -adverse unintended effects (iatrogenic) -intentional poisoning -nutrient overload/misuse

fluoride treatment

-best to prevent

pharmacology and toxicology share many common principles including

-biodynamics of uptake and elimination -mechanisms of action -principles of treatment -dose-response relationships

sources of copper: ruminants

-dietary supplements -water -disinfectants -mineral blocks copper/molybdenum/sulfur interactions copper additive; when looking for source of excess copper, don't just look at the feed

Top 10 ISU VDL Toxic Dx: First 50% all cases

-lead (Cattle) -copper (sheep) -anticoagulants (K9) -ethylene glycol (K9)

toxicokinetics of anticoagulants

-oral absorption; peak levels within minutes to several hours

1 ppm

1,000,000 ppt

selenium bioavailability and metabolism

1. Absorbed relatively efficiently (35-85%) (depends on the form) 2. Plant selenium more bioavailable Typically in organic form 3. Elimination is primarily via urine and feces

treatment for strychnine poisoning

1. Supportive - respiratory support 2. Control seizures - pentobarbital, diazepam, methocarbamol, gas anesthesia; seizures will kill the animal 3. Decontaminate: Gastric lavage; Activated charcoal 4. Fluids - diuresis, acidification of urine will help ion trapping of strychnine do not wait to get results--treat patient ASAP most cases from places like Wyoming onset so quick, emesis? one of those where you have to be careful. not advisable in this case. gastric lavage best option ; lightly anesthetized Primary goal - prevent asphyxia. Pentobarbital - the preferred drug for relaxation; given to effect with care. It is essential to be ready to intubate and administer artificial ventilation in severely affected animals. Robaxin (methocarbamol) at 150 mg/kg, IV, repeat doses of 90 mg/kg as needed has been recommended by some authors. NOTE: unnecessary when using pentobarbital. Inhalation anesthetics. May have to maintain in anesthetized state up to 48 hours. Contraindicated: Ketamine - due to motor stimulatory effects. Morphine - due to respiratory depression, possible stimulation of spinal cord. Artificial respiration if hypoxic. Detoxification - can shorten course - lessen severity. Emetics are generally contraindicated due to the risk of initiation of a seizure and aspiration. Enterogastric lavage. Activated charcoal and a saline or osmotic cathartic. Fluids, forced diuresis with 5% mannitol in 0.9% normal saline at 7 mg/kg/hour. Ammonium chloride (100 mg/kg, BID, po) to acidify urine thereby increasing protonation of strychnine reduce its reabsorption across the renal tubular membrane. NOTE: Ammonium chloride is infrequentl needed and is contraindicated if the animal is acidotic from exertion or from respiratory failure due to tetany of the muscles of respiration or when myoglobinuria is present. If the animal has a severe metabolic acidosis, the slow infusion of fluids with added bicarbonate is indicated. If acidosis is of respiratory origin, administration of bicarbonate is inappropriate. Experimentally, Sargiah (1985) found that diazepam, glycine, and beta-alanine given IP raised the seizure threshold in mice. However, in another report, glycine given to mice in high doses (1 - 6 g/kg, IP) caused hypothermia and sedation but was incapable of preventing strychnine convulsions (Lapin, 1981). Further evaluation of glycine and other amino acids is required before they can be recommended. Cardiovascular effects, if they occur, can be abolished by combinations of alpha- and beta-adrenergic blocking agents and can be reduced significantly by diazepam. Specific therapy depends on EKG and clinical signs. Care must be taken with any manipulation of the patient due to the excessive muscle stimulation and reflex rigidity that may readily occur.

I gram of chemical per ton of feed is equal to

1.1 ppm

1 ppm

1000 ppb

gastric lavage requires

anesthesia, airway protection

poison

any solid, liquid or gas that through either oral or topical routes, can interfere with life processes of cells of the organism. This interference occurs by the inherent qualities of the poison without mechanical action and irrespective of temperature -molecular level, organism, or population

prevent this in compromised patients when using AC

aspiration

public health concern for rodenticide toxicity

Secondary toxicity is probably not a factor when rodents who have consumed rodenticide anticoagulants are eaten by dogs or cats

serious poisoning of of phenoxy herbicides?

Serious poisoning rare unless concentrate or tank mix is consumed

clinical features of rodenticide toxicity

Signs are secondary to location and severity of hemorrhage/anemia o General signs usually 3-5 days after ingestion (can be as short as 1 however) depression anorexia generalized abdominal discomfort fever o Pale mucous membranes o Ataxia o Epistaxis o Dyspnea hypoxia pulmonary hemorrhage hemothorax o Hemetemesis o Melena/hematochezia o Lameness o Icterus large hematomas hemarthrosis breakdown of blood components with hemorrhage hypoxic liver damage o Sudden death with or without any presenting signs cerebral hemorrhage hemothorax cardiac tamponade o Abortions

mechanism of action of acute copper toxicity

Susceptibility to hemolysis by toxicants - Hexokinase is rate limiting for RBC glycolysis. It is inhibited by oxidized glutathione (GSSG), 2,3 DPG - NADPH reduces GSSG to GSH. Aging cell with limited hexokinase activity has less NADPH necessary to regenerate reduced GSH - After acute drug induced hemolysis, the younger surviving population of RBCs is less susceptible to further oxidative damage Sheep and goats have low G-6-PD activity and are *highly sensitive to copper induced hemolysis*

dinitrocompounds cause

Tachypnea, weakness, ataxia, disorientation, *hyperthermia*

How much is 1 penny compared to $10,000 ?

There are 10 pennies in a dime and 10 dimes in 1 dollar = 100 pennies/dollar Pennies in $10,000 =10,000 dollars x 100 pennies/dollar = 1,000,000 pennies Thus, 1 penny in 10,000 dollars is 1 ppm

heart worm therapy with arsenic

Thiacetarsamide Vomiting liver and kidney damage

phenoxy fatty acids

dioxin carcinogenic

True or False? Pyrethrins are more environmentally stable and more potent than Pyrethroids?

false

birds absorb chemical through

foot pads

rodenticide formulations

grain baits, weatherized blocks, tracking powders, water mixes

for example, concentrations of drugs and micronutrients in animal feeds are expressed as pounds or

grams of drug per ton of feed

an essential trace element and component of xanthine oxidase for purine metabolism

molybdenum

NOAEL

no observed adverse effect level

risk factors for zinc toxicity

o Dogs most often affected also cats, ferrets, pet birds o poisoning relatively unusual in large animals

lesions for zinc toxicity

o Hemorrhagic gastritis o Proximal renal tubular necrosis can be seen in dogs o Centrilobular hepatocyte vacuolization, necrosis

effect of vitamin D on renal

o Tubular degenerationPU/PD and hyposthenuriaazotemia o Hypercalcemiareduces cAMPADH action on tubules is altered decreased NaCl absorptiondiuresisazotemia

Widely distributed, little accumulation in fat. Short half-life, not appreciably metabolized, excreted in urine. Not accumulated in milk.

phenoxy herbicides

therapeutic index (TI)

ratio of the LD50 to the ED50 (TI=LD50/ED50)

• Extract of Derris root

rotenone

sorbitol cathartics relatively

safe, effective

emetics more effective if

stomach has some fill

AC less effective for

*ionized salts and metals*

toxic differentials for nicotine intoxication

- Chlorinated pesticides, - strychnine, - Pyrethroids, - Zinc phosphide, - OPs, Carbamates, etc

clinical signs of phenoxy toxicity in dogs

- Vomiting, diarrhea - *Myotonia*, ataxia, *posterior weakness, periodic clonic spasms - Abnormal electromyogram (EMG) - (dd ionophore toxicosis in dogs)*

clinical signs of chlorinated hydrocarbon toxicity

- acute (onset several hrs ...12 - 24) • Behavioral changes...belligerent, apprehensive Hypersensitive, walking backwards (cattle), chewing movements • Muscle tremors, especially face, head, neck • Tono-clonic convulsions ....intermittent CNS depression

treatment of inorganic arsenic

- most attempts are futile - rehydration - BAL (dimercaprol) is classic antidote but....best if used before signs occur - Thioctic acid (50 mg/kg q8h) - Succimer (DMSA) same as for lead tox (potential for small animals)

diagnosis of selenium poisoning- acute

- post mortem... *wet heavy lungs - chemical analysis...* > *4 ppm Se in liver tissue* In acute poisoning blood Se levels can reach 25 ppm Post mortem wet heavy lungs multiple organ necrosis Chemical analysis more than 4 ppm Se in liver tissue

prevention for selenium poisoning

- use correct injectable Se product, dose ◦ best to supplement Se through feed, mineral

mercury history

-Long history of toxicosis & pollution -Toxicoses infrequent and sporadic *cases in last 30 years associated with Hg fungicide treated seed *now cancelled for most uses in USA Current problems are mostly environmental pollution

ways selective poisoning is beneficial

-antibiotics -disinfection -pesticides (weeds, bugs, rodents) -cancer chemo (good vs bad cell)

diagnosis of thallium toxicity

-urine thallium (any is significant) -kidney or liver -feces

factors affecting poisoning outcome: dose

...

clinical signs of iron toxicity

1. 0 - 6 hours...corrosive effect - nausea, vomiting, diarrhea, g.i. hemorrhage 2. 6 - 12 - 24 hours apparent remission 3. 12 - 24 hours...in severely poisoned dogs severe lethargy recurrence of g.i. signs metabolic acidosis liver necrosis coagulopathy cardiovascular collapse, shock 4. Several weeks later... scarring and stricture of g.i. tract

1 ppb

1000 ppt

source of phenoxy fatty acids

2,4-D: dichloro-phenoxyacetic acid 2,4,5-T: trichlorohenoxy acetic acid Silvex: trichlorophenoxy propionic acid *Sometimes contaminated with dioxin:*tetrachlorodibenzodioxane; TCDD

amitrax toxic oral dose

20 mg/kg

anticoagulant that are more potent (lethal dose in single feeding) and longer acting

2nd generation

The toxic dosage of mercuric chloride in cats is 1 mg/kg/day for 15 days. What is the cumulative toxic dose in a 10 lb cat?

67 mg/kg change to kg then multiply by 15

emesis contraindications

Already vomited Caustic chemicals (pH < 4 or > 10) Volatile hydrocarbons Seizures

• Methoprene (insect growth regulator)

Altosid®, Apex® *prevents larval (metamorphosis)* development into adult fleas, flies, moths, mosquitos, etc - applied to premises... granules, etc - K-9 oral LD50 is > 5000 mg/kg sold in products with products targeting adults (pyrethrins and pyrethroids); look at active ingredients. may be issue in cats.

clinical signs of phenoxy toxicity in cattle

Anorexia, rumen atony, diarrhea, *bloat*, oral ulceration, rumen stasis

diagnosis of paraquat toxicity

Assay: Urine - persists 2-3 d post expos. - Solutions or baits as sources - Stomach contents

avicides

Avitrol Starlicide

a rodenticide developed in response to worldwide rodent resistance to anticoagulants

Bromethalin o Available for use in 0.01% concentrations of bromethalin in place packs weighing 16-42.5 gms Pellets are usually tan or green Relay toxicity can occur in cats that eat poisoned rodents Bromethalin is used less commonly than anticoagulants or cholecalciferol rodenticides and toxic exposures are rare but severe

Previously uncommon rodenticide with serious consequences to dogs and highly toxic to cats

Bromethalin; suitable alternative to brodifacone?

strychnine toxicity

Dog most sensitive@ LD50 0.5 - 1.2 mg/kg BW Cat LD50 2 mg/kg BW Approximate lethal doses. (Primarily from Kirk's Current Veterinary Therapy, Volume VIII, p. 98. - Available from amazon.com -). Bovine 0.5 mg/kg Equine 0.5 - 1.0 mg/kg Porcine 0.5 - 1.0 mg/kg. Canine 0.75 mg/kg. Feline 2.0 mg/kg. Rat 3.0 mg/kg. Fowl 5.0 mg/kg. Mallard ducklings 2 mg/kg. Pheasants 24.7 mg/kg. Thus based on 0.3% bait, 3 grams of bait would be potentially fatal to a 12 kg dog. steep dose-response curve so that any animal displaying clinical signs must be carefully attended.

principals of diagnosis: history

Gather Basic Information Names and addresses, Spp, breed, sex, age, wt # in herd, # affected, # dead Course of events-- acute, hyperacute, chronic, etc Feeding program: Any recent changes? Is a nutritionist involved? Immunization records: is the vaccination up-to-date? Past illness and treatment records Any changes in husbandry? e.g. temporary caretakers? new employees? Ask questions to explore the environment e.g.. use of pesticides, paints etc • Physically check the water, feed, pasture for clues (farm visit) • Estimate the degree of exposure. - Calculations to determine the dose of exposure.

diagnosis of metaldehyde

History of exposure Acute neurologic signs with hyperthermia & parasympathetic characteristics Stomach contents, bait, serum, urine for diagnostic testing for metaldehyde Keep samples frozen! History of exposure Although not readily available, in some labs metaldehyde can be detected in stomach contents, liver specimens, urine or serum Pathological Findings o Nonspecific o Stomach contents and breath may smell like acetylene or alcohol

4-Aminopyridine (Avitrol®) chemical analysis

ISU VDL Convulsant Panel : Strychnine Nicotine Caffeine 4-Aminopyridine More economical when history and signs don't suggest a single assay

acute lethal toxicity

LC501 or concentration in feed or water that will kill 50% of animals exposed

Dx of rotenone

Look for toxin...vomitus, blood, urine, feces

differentials for strychnine poisoning

Lots: Tetanus, metaldehyde, penitrem A, roquefortine, 4-aminopyridine, theobromine, nicotine, caffeine, amphetamines, cocaine, OPs, carbamates, pyrethrins, mushrooms, blue-green algae, chlorinated hydrocarbon pesticides, salt. Analytical tox results are helpful

toxicokinetics of metaldehyde

Low water solubility; insoluble in fat Absorbed intact from GI tract Uncertain metabolism -older literature says it forms acetaldehyde Cyt P450 inducers protect against toxicity t 1⁄2 in Humans is 27 hrs Acetaldehyde believed converted to CO2 and exhaled

surgical considerations for rodenticide toxicity

May need surgical intervention for hemothorax or other life-threatening hemorrhage but must be delayed until coagulopathy stable

slow onset cathartics

Mineral oil and bulk laxatives

diagnosis of Molybdenum toxicity

Mo levels >5 ppm in liver; and > 0.1 ppm in blood; Cu levels <10 ppm in liver and <0.6 ppm in blood

toxicity of phenoxy herbicides

Muscle: Decrease in chloride conductance (canine) Inhibition of ribonuclease synthesis - affects protein synthesis Uncoupling of oxidative phosphorylation weak hind quarters, wobbly

histopath of paraquat toxicity

Necrosis of Alveolar Type I epithelium, Emphysema, fibrosis in extended cases - Moderate renal tubular degeneration

treatment of dinitrocompounds

No specific antidote Support ventilation, oxygen *Thermoregulation*

Insecticides

Organochlorines Pyrethroids Organophosphates & Carbamates Imidocloprid Fipronil Amitraz Nicotine

differential diagnosis-bromethalin

Other conditions that impair the CNS (trauma, neoplasia, metabolic disorders, other toxins)

clinical signs of nicotine toxicity

Overstimulation of cholinergic receptors ● Initial stimulation and excitement, excess salivation, emesis, diarrhea, rapid respiration • marked muscle tremors and twitching rapidly progressing to muscle weakness and *paralysis*; similar to organophosphate poisoning in terms of presentation • Convulsions, depression, *shallow rapid respiration*, collapse, coma

nicotinee

Plant alkaloid Nicotine - from Nicotiana tobacum (2-8% nicotine in dried leaves) • tobacco products... cigarettes - 15 - 30 mg each (3-8 mg in low yield) cigars - 15 - 40 mg chewing tobacco - 2.5 - 8 mg/ g dry material ● insecticide, nicotine sulfate dust (0.5 - 4 %) • animal restraint • nicotine gum (Nicorette®) - 2 mg/stick • transdermal patches - 15 - 52 mg; well absorbed through skin

metabolism of phenoxy herbicides

Readily absorbed, excreted in urine (18 hr T1/2) • Alter metabolism of plants - Increase nitrate content - Toxic plant palatability

diagnosis of chronic selenium poisoning

Se in whole blood, serum, liver, feed or forage Se in hair Se in hoof wall

activity level for rodenticide toxicity

Strictly limited until coagulopathy is resolved

common differentials for metaldehyde poisoning

Strychnine - acute, tremors, rigidity Zinc phosphide* - vomit, running, seizures Bromethalin - delayed signs, tremor, ataxia OP-Carbamates*- SLUDD signs + tremors Pyrethrins - acute, continuous tremors 4-Aminopyridine - HR, tremors, hyperesth. Penitrem A* - diarrhea, tremors, temp Blue-green algae (Anatoxins)- peracute, salivation, diarrhea

mechanism of toxicity of dinitrocompounds (used by people for weight loss)

Uncouples oxidative phosphorylation:* Prevents conversion of ADP to ATP*

acute oral LD5o in dog (mg/kg) for anticoagulants

Warfarin (1st gen) 20 - 300 Brodifacoum 0.22 - 4 LD10 = 0.20 Bromadiolone 11-15 Diphacinone 0.9 - 8

toxicodynamics of paraquat

Water soluble Limited absorption (~20%) *Excreted in urine as unmetabolized compound* Concentrates in the pulmonary tissue (10-fold greater than other organs)

specimens from live animals

Whole blood, serum Urine Vomitus Fat biopsies Hair

clinical signs of rodenticide poisoning manifest

72 hours after a typical anticoagulant rodenticide exposure

2. Decontamination with *Adsorbents*.. agent of choice?

activated charcoal

activated charcoal funciton

adsorbs organic materials in GI tract

toxic

describes the effects of a poison on living systems -"toxic effects of arsenic are related to the GI system and kidneys" (GIT and kidneys are target organs)

acute toxicity

describes the effects of a single dose or multiple doses during a 24-hr period.

anticoagulants primarily affect

dogs, wildlife but others including food animals are susceptible

ED50 (effective dose 50)

dosage of a drug or therapeutic agent that produces the desired effect in 50% of a population

factors affecting poisoning outcome: breed

e.g. ivermectin toxicosis in collies; Brahman bulls more sensitive to organophosphates pesticides than Herefords • Collies have defective MDR1 gene which helps pump ivermectin from brain across BBB ○ Can't pump ivermectin out so ivermectin accumulates Other animals can pump it out

factors affecting poisoning outcome: physical nature

e.g. powders vs. pellets • Sometimes same toxicant can be in different forms ○ Generally powders have more surface area--is it absorbed? Cross integumentary system whereas pellets don't Pellets: takes longer to dissolve than nanoparticles (powders)

clinical signs of arsenic toxicity

effects g.i. tract... vomiting intense abdominal pain diarrhea (may be bloody), fluid loss maybe acute death (hours) marked dehydration weakness, staggering gait

Multiple AC may reduce

enterohepatic cycling

Selenium component of

enzymes glutathione peroxidase, thioredoxin reductase, and others. Essential trace element ◦ Cellular antioxidant (similar to vitamin E) ◦ Glutathione reductase, thryoxine formation ◦ Related to sulfur - competes with S and can replace sulfur in sulfur amino acids Overdoses can be toxic Modern problems are related to production animal medicine, dietary supplements and potential environmental pollution

median lethal dose (MLD)

equivalent to the LD50 and can be used interchangeably with it

avoid gastric lavage when

esophagus/stomach injured

Pyrethrins

extracts of Chrysanthemum, not very stable -natural product

which lavage should you retain?

first lavage

exposure and effects of toxicants are often defined by the

frequency and duration of exposure: acute, subacute, synchronic, chronic

where emesis is not recommended (coma, seizures, corrosives, vomiting limited) use

gastric lavage;

metaldehyde lesions

general, difficult to interpret GI inflammation Hepatic, renal, pulmonary congestion/hemorrhage - non-specific Stomach Contents: odor of acetylene (or like alcohol breath) Histopathology: Hepatocellular swelling, neuronal degeneration - non-specific

help clients by providing

good risk analysis

Bromethalin Bait Blocks

have a stop feed action, which prevents bait hoarding, and are highly appealing to rodents come in a resealable plastic tub to keep bait fresh

majority of toxicants (90%)

have no specific antidotes

vitamin D Interactions with Drugs, Nutrients, or Environment

high fat, high calcium diets

Saline cathartics (Na, Mg) traditional, but caution for

hypermagnesemia

mercury chemical form determines clinical effects..

inorganic: GI and renal tubular necrosis organic: neurologic; fibrinoid degeneration of arterioles, neuronal necrosis-->blindness, staggering, incoordination, recumbency, death; *organic form crosses BBB and placenta*

Type 1 vs Type II pyrethroids

insects more sensitive to mammals to pyrethroids and pyrethrins: although mechanism similar, the enzyme of these compounds more potent at lower body temperature than higher body temperatures.

primary targets of mercury

kidneys and CNS

excretion of mercury

kidneys-->urine; fecal, lungs

non-selective herbicides

kills everything (plant) e.g. Roundup (glyphosate), arsenicals, Paraquat, chlorates

post emergent herbicides

kills growing animals

highest nontoxic dose (HNTD)

largest dose not resulting in clinical or pathologic chemical-induced alterations

why is mercury an unusual metal

liquid at normal temperatures -vapor poses hazard -inorganic and organic forms exist

Case 5: 6 yo dog was in bean field and got sprayed. dog exhibit tremors and hypersalivatio. owner brings for exam. you suspect OP/carbamate poisoning

mechanism of OPs/carbamates: inhabit acetylcholinesterase administer of atropine: what can tell your diagnosis was correct: pupil exam of eye reveals pull to be constricted treat with atropine

standard safety margin

more conservative and clinically relevant estimate than the TI; the SSM is the ratio of the LD to the ED99 (SSM=LD1/ED99)

selenium safety margin

narrow margin of safety • i.e. small difference between deficiency and toxicity in terms of dietary intake

selenium deficiency diseases

nutritional muscular dystrophy (NMD) in lambs, poultry, pigs and calves a lot of environments don't have selenium so we have to supplement. so toxicity usually due to error in addition of selenium to feed

pharmacokinetics metaldehyde

o Absorbed from the gastrointestinal tract intact poorly water soluable and insoluable in fat o Readily crosses the blood brain barrier o How metabolism occurs is unknown may involve cytochrome P450 enzymes as inducers of these enzymes are protective against toxicity acetaldehyde conversion to CO2 is likely and probably eliminated with respirations o T1/2 is unknown in animals and is presumed to be 27 hours in humans based on one case of human poisoning

Warfarin resistance led to more potent second generation formulas usually as 0.005% concentrations including:

o Brodifacoum (Most commonly sold, highly toxic) Talon, Havoc, Bolt, Volid, D-Con Mouse-Pruf II o Bromadiolone Maki, Contrac, One-Bite, Hawk o Diphethialone D-Cease, Hombre, Generation

toxicity of bromethalin

o Cats are much more susceptible to toxicity o Repeated exposures could cause toxicity at lower doses

keep measurement units

organized and consistent

metals are

persistent; do not degrade

- As a group, these are the most commonly used herbicides.

phenoxy fatty acids

- Post-emergent control of broadleaf weeds. - Analogs to plant hormones.

phenoxy fatty acids

lead absorption

poorly absorbed 2% from GI tract

pre-emergent herbicides

prior to seed germination

chronic toxicity

produced by prolonged exposure for 3 months or longer--often lifetime for carcinogenesis

modern selenium problems related to

production animal medicine dietary supplements and potential environmental pollution

chronic exposure to fluoride

progressive debilitating disease (cattle, horses, wild herbivores) may increase remodeling of bones -osteofluorosis: bone formation on outside of long bones (exostoses) produce lameness. medial areas of metatarsal and metacarpal areas. running hand over these areas--feel incongruence because abnormal bone growth. mandibles also become involved early on. ribs too. chronic poor doers; losing condition because of abnormal wear and tear of the teeth (feel pain when chewing); lap water because teeth very sensitive -dental fluorosis: softening of tooth enamel, early wear; leads to mastication problems. mottled teeth due to oxidation of proteins in poorly formed teeth. when chewing on roughage, sensitive part of teeth exposed-->hamper mastication and drinking water -poorly crosses placenta so it doesn't affect fetus

vitamin D toxicity: neuro signs

rarely seizures

rodenticides target

rats, mice, gophers, moles

use _______ figures for feed or water intake

realistic

environmental impact of anticoagulant poisoning

relay toxicosis (poisoning by eating a poisoned animal) seen in avian species brodifacone? --should only be given by licensed applicators restricted to pesticide applicators. Recommending use of first generation of anticoagulant rodenticides in market

subacute toxicity

repeated exposure and affects observed for 30 days or less

safety of ______ often ignored

rodenticides (occasional malicious poisoning)

Empty stomach ...emetics Early/At home - not with

seizures, coma petroleum distillates, caustics

Herd treatment of copper toxicosis in sheep may be accomplished by feed supplementation with molybdates and sulfates. Use of molybdates alone reduces copper uptake by 0.5%. Addition of sulfates alone reduces copper uptake by 31%. But addition of both molybdates and sulfates simultaneously reduced copper uptake by 62%. Select the one correct answer

synergistic

herbicides

target weeds • > 125 chemicals in several chemical classes • Generally low mammalian toxicity as a group; not as potent on mg/kg BW exposure generally don't get issues when animals walk on grass with herbicides issues when directly sprayed or drank from buckets with herbicides

2 types of thallium

thallic +3 thallium +1

dosage

the amount of toxicant per unit of animal weight

the clinical veterinary toxicologist is a specialist in

the cause, identification, and treatment of animal poisoning

To convert percentage to ppm,

the decimal place is moved four plates to the right (i.e., 1.0% = 10,000 ppm).

True or False? Both selenium and thallium cause alopecia in animals

true

In the 1940's further research found a more potent analog to dicoumarol,

warfarin

plasma half life of anticoagulants

warfarin: 14 hr diphacinone: 4.5 days brodifacoum: 6 days

limit gastric lavage fluid to

water/saline at 5-10 ml/kg/dose

better candidates for enhanced excretion because they tend to remain in plasma (have smaller volumes of distribution) which has a higher pH (7.4) than intracellular fluids (pH = 7.0).

weak acids

functional antagonism

when two chemicals produce opposite physiological effects e.g.. hypotension caused by barbiturate overdose Vs vasopressor effects of norepinephrine; or strychnine, a convulsant Vs diazepam, an anticonvulsant

Which of the following is NOT typical of a cholecalciferol intoxication diagnostic profile?

zinc

toxicological properties of metal

• Cumulative in biological systems • Can change valence • Complex with organic molecules • Persistent in environment • Can be strong oxidants • Bind to essential molecules • Many metal-to-metal interactions • Clinical toxic effects vary widely

Why do compounds that are rapidly metabolized have about the same chronic LD50 as the single-dose LD50?

because rapidly excreted compound has little opportunity to accumulate in the body

Asulum, Asulox Herbicide preparations are less toxic than carbamates used in insecticides

carbamates (chloropropham) (herbicide)

generally use these only once with first AC dose

cathartics

active ingredient in rampage

cholecalciferol ppm is 750 ppm (multiply by 10,000)

list of pesticides

1) Rodenticides 2) Insecticides 3) Molluscicides 4) Avicides 5) Herbicides 6) Fungicides 7) Algaecide pests are the unwanted species

mechanism of toxicity of paraquat

1) Selective uptake by alveolar cells (diamine-polyamine transport Paraquat molecule = PQ++ system) 2) Single electron reduction to form a free radical PQ++ + NADPH ----> PQ+ (radical) + NADP+ 3) Oxidizes molecular oxygen to superoxide; returns paraquat to original form PQ+ (radical) + O2 ----> PQ++ + O2- potent respiratory toxicant

arsenic toxicokinetis

1. Absorption of different forms is variable. This is a major factor in toxicity. 2. Distribution a. Accumulation initially in liver and then slowly distributed to other tissues (such as spleen, liver, and lung) • later accumulates to keratinized tissue b. Crosses placenta and is embryotoxic c. Crosses blood-brain barrier d. Hair and keratinized tissue, • Eliminated in the feces and urine. Inorganic Arsenic Toxic Mechanisms: • binds with sulfhydryl enzymes • blocks cellular respiration - acts on tissues with high respiration i.e. gut epithelium, capillaries • Toxicity: Trivalent is 5-10 X more toxic than pentavalent Arsenite (+3) > Arsenate(+5) > organic As

Insecticides Opportunities for poisoning...

1. Accidental incorporation into feed - Unintended application to crops or forages -Left-over chemical put in different or unlabeled container ...often mistaken for feed ingredient 2. Mis-use or mis-calculation for external parasite control ...sprays, dips (concentrates have to be diluted to right dip), pour-on, spot-on, collars ● Improper use of chemical ● Not reading the label 3. Low level exposure to persistent insecticides esp. in wildlife ...residues, cumulative 4. Accidental access to insecticides by animals - improperly discarded or mis-used products - access to storage areas 5. Malicious poisoning

Estimating dosages when exposure is based on consumption of green forage that has been sprayed

1. Forage crops used for hay or pasture may be sprayed with a potential toxicant prior to use by animals for food and resulting residues may be suspected of causing toxicosis. 2. Sampling and analysis can provide an estimate of exposure, but sometimes an immediate, "on site" estimate can be useful in interpreting the probability of poisoning. a. Information used to estimate chemical intake from sprayed forages includes: (1) Amount of forage eaten by animals at risk (2) Application rate of chemical per acre or hectare (3) Yield of forage per unit of land sprayed b. The contribution of 1 lb of chemical per acre to the diet of a forage-consuming animal can be calculated as follows:

Other considerations in assessing intoxication...

1. Formulation - liquid vs. dry granular or powder 2. Toxicity... inherent toxicity i.e. 3 mg/kg; variation in terms of toxicity on mg/kg body weight of different compounds even within same category. wide range of LD50's within that category 3. Crop vs. animal products Crop & horticultural products more hazardous due to formulation - small particle size; vehicles or solvents for liquids. Formulated to stick to plants; if accidentally fall on animals, sticky. 4. "Restricted Use" Pesticides Restrictions may be due to - Extreme toxicity - Long residue half life - Special skills needed in application

sources of arsenic

1. Mining sites and smelters 2. Insecticides and herbicides 3. Wood preservative 4. Medicinal (heartworm therapy) 5. Feed supplements (organic arsenicals/phenylarsonic) inorganic arsenic: - Old pesticides...lead arsenate, herbicides (herbicide "liquid edge" is inorganic arsenic) - Terro® ant poison ashes of CCA lumber - Toxicity ranges 25 - 100 mg/kg

selenium method of action

1. Production of J*free radicals →oxidative tissue damage* 2. *Displacement of sulfur* from proteins • Selenocysteine and selenomethionine are similar to cysteine and methionine, -*Likely mechanism in hair and hoof lesions of chronic toxicosis* ●*Depress ATP synthesis;* vascular damage

Cholecalciferol Diagnostics

1. Serum calcium > 12 mg/dL (serum phosphorus may also be increased) - do baseline Ca initially -recheck in 12 hrs (begin to see whether you get increase in serum Ca) 2. Bradycardia 3. Urine specific gravity @ 1.002 - 1.006 4. Increased BUN and creatinine 5. Increased vitamin D metabolites: 25- dihydroxy D3 (other DDx not increased) 6. Serum iPTH is suppressed 7. Lesions of tissue mineralization - kidney, stomach, 8. Kidney tissue calcium and phosphorus level - with toxicosis... - Ca elevated to 2000 - 3000 ppm (normal < 600) - Ca/P ratio elevated @ 0.4 - 0.79 (normal < 0.2) DDx: -Hypercalcemia of malignancy* -chronic renal failure**; -primary hyperparathyroidism**, -Feline indiopathic hypercalcemia. *Serum PTH decreased **Serum PTH increased

phases of chronic copper poisoning in sheep

1. accumulation phase -weeks to months -copper stored in liver (lysosomes) -*no clinical effects* except slight decrease in rate of gain 2. acute hemolytic crisis - after release of copper from liver - distessmaytriggerrelease - hot weather, moving, showing, etc. - animals are depressed, anorectic, weak hemoglobinuria, icterus -*oxidative stress*

mechanism of action of arsenic

1. arsenite - As3+ inhibits ATP synthesis Sulfhydryl inhibition (enzymes) α-Lipoic acid - TCA cycle 2. Phosphate competition - uncouples oxidative- phosphorylation 3- (Arsenate-As5+) resembles Pi in structure and reactivity, replaces phosphate Arsenic is eliminated/detoxified rapidly compared to other heavy metals; Most intoxications are acute or subacute.

mercury and environmental concern. there are three different forms in the environment:

1. elemental mercury (Hg; metallic or vapor) 2. mercury salts (inorganic mercury) e.g. HgCl2 3. organomercurial compounds (alkyl forms=ethyl, methyl, propyl, dimethyl, etc. and aryl forms of mercury such as phenyl mercuric acetate -mercury accumulates as alkyl (methyl, ethyl) mercurcy

assumptions for dose-response

1. response is due to the chemical administered or exposed: may only be an "association with" in retrospective or clinical studies where dose & duration are seldom quantified 2. magnitude of response is related to dose ; dose-->conc. at target site-->chemical effect at target site-->response of organ or tissue 3. Quantifiable method of measuring the toxic endpoint ...ideally, related to molecular events produced by toxicant But, often use secondary or effects-related biormarkers...AChE, AST, etc. or "clinical response"

factors affecting poisoning outcome: enrivonmental factors

1. season: fescue toxicosis 2. transportation: Cu in sheep 3. noise: strychnine 4. water: quality and quantity • Fescue foot: more common in the foal or in winter, vasoconstriction causes necrosis of foot • In summer have heat intolerance: standing in pools of water, seeking shade • Some intoxications triggered by stress such as copper toxicosis ○ Shipping, tracking ○ Could have accumulated a lot of Cu in system, delivered to new property and have 20-30 animals dead next day • Cold: animals going down with Cu toxicosis Sudden noise may trigger animals to undergo seizures in animals exposed to Strychnine

if in doubt, best to use this for decontamination

AC

zinc toxicity diagnosis

Abdominal radiograph to visualize coins or metal objects in stomach or intestine

mercury treatment

Acute exposure: Egg white, activated Charcoal; Sodium thiosulfate (0.5 1.0 g/kg) -saline cathartic or sorbitol -oral d-penicillamine (15-50 mg/kg orally) antidote for Hg -DMSA (dimercaptosuccinic acid) antidote for Hg excreted through urinary chronic organic....Se, Via E; recommended as antioxidants. watch out for chronic type mostly in cats fed fish

Case 1 -Fido is a terrier and the family pet brought into your cliic. Owners said he was more lethargic than usual and was having trouble breathing. Also noted he had a bloody nose. Exam: -Fido appears anemic and exhibiting epistaxis. -He continues to have difficulty breathing during exam. Lung and heart sounds muffled. -Owners say there is Rat poison at home (d-con) but no way Fido could get into it. Quiz: Age, Fido's weight, underlying conditions, environment would all be helpful upon presentation. What is the next step that should be taken?

Address respiratory issues. Possible hemothorax needs to be relieved ASAP. Then treat with administration of vitamin K1 (not K3). Whole blood transfusion option if sufficient blood loss--will have clotting factors. Administering emetics at this point would have no effect because it's too late. Rodenticides onset of clinical signs delayed, and by time signs observed, too late to administer emetic which should be given within a few hours of ingestion of chemical. Unfortunately Fido passes away on your exam table. Owner requests a necropsy and you see hemothorax, hemopericardium, hemorrhage with tissues. At this point what diagnostic sample would be the preferred choice for confirming anticoagulant poisoning? Liver. Anticoagulants accumulate in liver and metabolized there. Stomach contents not a good idea because already passed through GI system and little change original anticoagulant rodenticide in stomach because clinical onset of 24-48 hours.

Environmental and Food safety impact of Starlicide

All Avian species are targets. Mammals less so • Mass deaths reported in birds - 2009 Griggstown NJ hundreds of birds died - 2011 Deaths in Yankton, South Dakota. • Low probability for relay intoxications • Food safety impact is not known

rodenticides

Anticoagulants Cholicalciferol Zinc Phosphide Strychnine Bromethaline Metaldehyde

arsenic based fungicides green colored, pressure treated "outdoor wood" ...decks, play structures, fencing, animal facilities still a lot fence posts treated with arsenic presently see problems from bonfires and animals come a day later to lick ashes and end up with severe arsenic poisoning • CCA mixture generally ~ 25% arsenic • Low toxicity to animals, Arsenic "fixed" in wood... except if burned, ashes high in elemental arsenic • Public health concerns with arsenic as a human carcinogen ...so now phased out New products are copper salts - less acute toxicity

CCA - chrome copper arsenic (CrO3-CuO-As2O3)

Anion Exchange Resins to eliminate absorbed toxicants

Cholestyramine is used to reduce enterohepatic recirculation of some toxicants--- e.g. warfarin, digitalis glycosides, thyroid preparations

source of paraquat

Commercial preparations: Dextron X, Dextrone, Herbaxon, Toxer. Concentrated forms for agriculture (5-20%solutions). Diluted forms for domestic use. *Often mixed with diquat*

canine copper storage disease

Copper storage disease is a primary copper metabolism defect o Inherited (autosomal recessive) defect in copper metabolism o Liver disease is secondary to the defect in copper metabolism o Acute or chronic Secondary form of copper toxicity is a different entity o Cholestasis or other primary liver defect leads to accumulation of copper over time Familial, associated with specific breeds -Bedlingtons, Skye, West Highland, Doberman -Autosomal recessive trait (COMM1 in Bedlingtons) excretion -In Dobermans the female gender is predominant results in abnormal biliary -Chronic accumulation first noted in young adults -Manifests as chronic hepatopathy and/or acute hepatitis and icterus

metaldehyde prognosis

Death 4 - 24 hrs post ingestion Respiratory failure > 50% of cases die Early, aggressive detoxification and therapy essential

treatment for rotenone

Decontaminate; Diazepam; dextrose IV.; Oxygen.

second generation anticoagulants

Definition: Efficacious against warfarin resistant rats; warfarin not quite potent; requires multiple ingestions. Rodents stopped eating and developed resistance. Population of rats that became resistant-necessary to invent more potent anticoagulant rodenticides so second generation ones came in. Typical concentration is 0.005% • Brodifacoum (Most commonly sold, highly toxic) until 2 years ago - Talon, Havoc, Bolt, Volid, D-Con Mouse-Pruf II • Bromadiolone - Maki, Contrac, One-Bite, Hawk • Diphethialone - D-Cease, Hombre, Generation

diagnosis of strychnine poisoning

Detection of strychnine in... 1) Stomach contents 2) Urine - mildly acidic urine promotes Ion trapping 3) Liver Food or bait usually in stomach if recently exposed. Analysis of: Baits. Frozen stomach contents obtained by lavage or at necropsy in lethal cases are most useful. Frozen liver. Frozen urine. Urine is the primary route of elimination but some animals may die too fast to detect strychnine in the urine. Histopathology on brain should reveal normal tissue or perhaps changes consistent hypoxia.

Chlorinated HC Classifications

Diphenyl *aliphatics* (DDT, methoxychlor) • *Aryl* hydrocarbons (Lindane, mirex, kepone) • *Cyclodienes* (aldrin, dieldrin, endrin, chlordane, heptachlor) • Most are banned in USA except limited use of lindane. • Methoxychlor registration cancelled 2004 *different structures but clinical signs when exposed are about the same--typically neurotoxicants, hard to metabolize, long half life and accumulate in fat. all of them are characterized by stimulating the CNS and by being well-absorbed from skin and GIT and very cumulative.

Concentrations of drugs and chemicals are often expressed for commercial uses in the

English system of ounces and pounds.

function of copper

Essentiatrace element -required-->enzymes for Fe metabolism and mitochondrial function a. multiple-copper oxidases for Fe transport b. superoxide dismutase c. cytochrome c oxidase

metaldehyde treatment

Evacuate gut: gastric lavage, enemas 1. Stopabsorption...activatedcharcoal 2. Controltremors...diazepam,barbiturates (phenobarbital), methocarbamol, ketamine anesthesia Detox/Symptomatic/Supportive o Emetics early Remember not to give emetics to obtunded animals or those with other conditions predisposing to aspiration o Aggressive gastrointestinal decontamination significantly improves survival and shortens duration of treatment activated charcoal and saline cathartics gastric lavage o Control seizures diazepam or diazepam with phenobarbital barbituate coma ketamine anesthesia o Hydrate: LRS (40-90 mg/kg/hr) o Treat acidosis if: pH < 7.2 HCO3 < 17 in dogs; < 15 in cats o Na Bicarb mEq = 0.3 X BW(kg) X (desired - observed plasma HCO3) o Control hyperthermia IV fluids environmental control o Treat for potential liver damage

avitrol supportive therapy

Activated charcoal Maintain hydration: lactated ringers (40-90 mg/kg/hr); For Acidosis (if pH < 7.2): NaBicarbmEq=0.3XBW(kg)X(desired- observed plasma HCO3- ) Control hyperthermia

differential diagnoses for anticoagulant toxicity

Autoimmune thrombocytopenia Dicumarol - livestock eating moldy hay DIC Hereditary (Von Willebrand's Disease) Idiopathic coagulopathy Liver disease (decreased clotting factor synthesis, decreased plasma protein production)

key features of strychnine

Baits, malicious poisoning. Strychnine in stomach contents. Interferes with glycine at postsynaptic neuronal sites in spinal cord. Tetanic seizures, asphyxia, opisthotonus, rapid onset and progression in most cases. Pentobarbital or other anticonvulsant treatment combined with detoxification using activated charcoal and (sometimes) acidification of the urine while avoiding contraindicated drugs.

diet for rodenticide toxicity

Fatty meals will improve vitamin K absorption

Avicides

Fenthion (OP) perches Endrin (ChlHC) perches - cancelled in 1991

detoxification for rodenticide toxicity

If given within 3 hours and animal not recumbent can induce emesis o apomorphine (dogs) o xylazine (cats) o H202 (both) Activated charcoal Sorbitol

prognosis for chronic copper toxicity in sheep

Individual animal o prognosis very guarded o prognosis depends on kidney function Flock o herd morbidity <5% usually but of those affected >75% die

Pharmacokinetics / Absorption, Distribution, Metabolism, and Excretion of anticoagulants

Oral absorption - peak levels within minutes to several hours Plasma half lifewarfarin 14 hr; diphacinone 4.5 days; brodifacoum 6 days Accumulate and metabolized in liver Excretion via kidney and urine Some transfer to milk Placental transfer suspected

strychnine

Strychnine is a bitter tasting alkaloid extracted from the seeds of an Indian tree, Strychnos-nux vomica. Present in "Nux Vomica" medications and homeopathic preparations. Supposed ruminatoric but is ineffective. Not a ruminatoric. There is no logical therapeutic use. Present in pesticides to control: Gophers, moles (subsoil use) - Most products, especially those available OTC. Rats. Coyotes (not leagal in the USA). Infrequently relay toxicosis; may be more of a problem in raptors (Redig et al., 1982). Often dyed - red or green. Restricted in some states more than others. OTC availability - 0.5% (or 0.3%) or lower concentrations for subsoil use in the United States. All species are sensitive; problems mainly occur in small animals, especially dogs. Both accidental and malicious poisonings occur.

Selenium in History

The Battle of Little Bighorn was fought over 125 years ago but many controversies remain. A slow-moving pack train may have hindered the troops of Benteen and Reno from joining up with Custer. Horses and mules in the pack train were lame and behaved crazily. The lameness may have been caused by selenium, or by behavioral problems from locoweed. Vet Hum Toxicol. 2000 Aug;42(4):242-3 Farmers and ranchers in the 19th century on the American great plains observed chronic poisoning as a condition called "Alkali Disease" and another known as "Blind Staggers". Current understanding is that Alkali Disease was a form of chronic selenium poisoning in animals grazing on selenium concentrating plants, primarily Locoweed (Astragalus spp, Oxytropis spp, or on forages and grains that accumulated higher concentrations of selenium (See Selenium accumulator plants).

prognosis for lead toxicity

Usually good if diagnosed early and prompt therapy is applied Outcome dependent on good nursing and aftercare, e.g. maintain fluid balance, parenteral or oral tube feeding; stimulate appetite; supplement with multi-vitamins.

1. stabilizing the vital signs

"Keep the patient alive" i) Ensure adequate respiration Ensure the airway is patent. Use a respirator. Atropine in case of secretions ii) Support cardiovascular system Volume replacement—Blood, fluids to prevent shock. Correct cardiac arrhythmias Consequences of cardiac arrhythmias include-- weaknesses, dyspnea, depression Cardiac arrhythmias: Treat underlying cause e.g.. for acid-base/electrolyte imbalances, use tailored fluids e.g.. for Hyperkalemia-- saline or sodium bicarbonate For sinus bradycardia use Atropine or glycopyrrolate For AV Block—use Atropine iii) Correct acid-base imbalances Acidosis—Caused by seizures, shock, depressed respiration, acidic toxicants and/or their metabolites. More common than alkalosis. Consequences of acidosis include e.g.. tachypnea, vomiting, arrhythmias Rx: 1-3 mEq/kg sodium bicarbonate over 1-3 h by infusion Alkalosis: From excessive vomiting Consequences—Include tetany, arrhythmias. Rx with 0.9% normal saline iv) Seizures Causes -- e.g.. strychnine, chlorinated pesticides, theobromine, lead, etc Consequences-- hypoxia, acidosis, death Rx: Diazepam Pentobarbital/Phenobarbital Quite environment • Contraindicated: Phenothiazines e.g.. chlorpromazine v) Severe CNS Depression Causes e.g.. Barbiturate/opiate poisoning Consequences-- profound hypotension, respiratory depression, trauma Rx Analeptics e.g.. Doxopram; use a respirator vi) Additional Supportive Measures • Maintain adequate body temperature. This minimizes stress and ensures optimum conditions for metabolic enzymes.

metal

(Greek: Metallo, Μέταλλο) is a chemical element whose atoms readily lose electrons to form cations, and form metallic bonds* between other metal * atoms and ionic bonds with nonmetal atoms.

rodenticide sources of vitamin D

(most common) are pellets, granules, flakes, cakes, etc. in formulated in 0.075% concentrations o Rampage®, Quintox®, Ortho Mouse-B-Gone® o Used in "place packs" @ 10 - 30 grams each o Marketed as single feeding or chronic o Toxicosis in rodents delayed 2-3 days after single ingestion - reduces bait shyness o 1 IU of D3 = 0.025 ug cholecalciferol

first generation anticoagulants

(often contain 0.05% ) • Warfarin: first to be discovered following investigations of death in livestock which were folding on moldy hay/sweet clover which contains? Fungus dimerizes coma dine? into dicomer? When dimerized, with help of fungi, get dicomero? an anti coagulants • Diphacinone: Tomcat, Ramik, Mousemaze • Chlorophacinone: Rozol

Hydramethylnon

*Metabolic inhibitor, stops ATP synthesis in insects.* • (Roaches and ants) • *Combat®, Amdro®* (roach motels) • *Low toxicity for mammals* - rat LD50 - 1130-1300 mg/kg ...20 kg dog would have to eat 240 trays before adverse effects - *mouth lacerations and/or foreign body from plastic trays*

4. Antidote to counteract mechanism....

*The majority of toxicants do not have specific antidotes. But if an antidote exists USE IT!* Antidotes are based on the principle of chemical antagonisms. can give antidote immediately, before decontamination if know what toxin is

species most susceptible to molybdenum poisoning

*cattle* -copper deficiency causes *reduced* stability and *strength of collgaen*, *reduced melanin synthesis* and compromised integrity of erythrocyte membranes -Mo may compete with phosphorous for mineralization of bone

use as an emetics

*hydrogen peroxide (variable, relatively safe) * syrup of ipepac (variable, difficult to administer) NO salt or dish detergents Apomophine (dogs, in clinic) IV, IM, S-conj, SQ Xylazine for cats (yohimbine for reversal)

Plants absorb water soluble

*molybdate*

Vitamin D2 (ergocalciferol)

*the plant derived form of vitamin D* Vitamin D2 crystals have a potency of 40,000 units of vitamin D (USP) per mg

Environmental and Food safety impact of zinc

*• Necropsy hazard!* • All animal species are targets • Mass deaths reported in birds • Potential for secondary intoxications exist • Food safety impact is not known

lead clinical signs in birds (pet birds, waterfowl)

- *depressed*, weak, *anorectic*, weight loss, *esophageal paralysis*, regurgitation, diarrhea - *Wing droop*

susceptible to OP's - carbamates

- All ( esp. cattle, swine, dogs, birds) - Cats more susceptible than dogs - Brahman cattle more than English - Bulls, other males more than females; high metabolic rate especially where oxygenation is required; more efficient in males - Poultry highly susceptible to dichlorvos (chlorinated organosphate pesticides) birds and fish very sensitive

Pyrethroid Classes: Type I (no ά cyano)

- Allethrin - Permethrin - Phenothrin - Resmethrin - Sumithrin - Telfluthrin - Tetramethrin

Lufenuron: Program® (insect growth regulator)

- Benzyl urea pesticide - *inhibits deposition of chitin in eggs and exoskeleton of fleas* - No effect on adult fleas -transferred to the eggs through females blood

Ddx for lead poisoning in dogs

- Canine distemper, parasites, - Methylxanthines, tremorgenic mycotoxins - NSAIDs (GI) - Salt toxicosis Canine distemper, ICH, parasites, pancreatitis, bromethalin, methylxanthines, tremorgenic mycotoxins, NSAIDs, water deprivation/salt toxicosis o GI vomiting , anorexia, tender abdomen, diarrhea/constipation o CNS lethargy, hysteria, convulsions, ataxia, blindness, mydriasis

public health lead concerns

- Children in household exposed to same lead source as pets • *Food safety* - Long residue time in bone - Transfer to *milk* in early lactation - Residues can vary from weeks to months - Contact state veterinarian recommended • Prevention: Owner/producer education FOOD SAFETY Long residue time in bone, can be mobilized by calcium deficiency or metabolic acidosis Transfer to milk in early lactation Residues in milk can vary from weeks to months Contact state veterinarian: recommended, required in some states Prevention: Owner/producer education Although the incidence of lead poisoning in animals is unknown, environmental control efforts have likely decreased the numbers of animals affected by lead poisoning o According to the CDC the number of U.S. children < 72 months tested for lead that were positive for significant lead levels (≥ 10 μg/dl) decreased from 7.61% in 1997 to 1.21% in 2006 which may indicate the number of small animals poisoning has decreased as well o The transition to unleaded paint and gasoline has decreased lead poisoning in all species

toxic differentials of OP's and carbamates

- Chlorinated pesticides, - strychnine, - Pyrethroids, - Zinc phosphide, - nicotine, etc many cause CNS excitation. generally clinical signs for chlorinated pesticides: don't see PNS signs but something to keep in mind. strychnine sample of choice: stomach contents or urine samples pyrethroids sample of choice: hair ; skin if animal dead or SQ tissue zinc phosphide sample of choice: stomach contents; make sure frozen

Help your chemist to help you best:

- Choose appropriate samples for analysis. - Be clear and specific about the tests you want. - Give a detailed history when requesting tests. - There is no single test for all toxicants and there are no tests for each and every toxicant. • E.g. some require bioassays, i.e. reproducing the disease in same species or other model e.g. botulism. • Excellent communication with your chemist/toxicologist will yield best results in a timely fashion.

Pyrethroid Classes: Type II (has ά cyano-increased half-life in tissues and envrironment; more stable than type I)

- Cyfluthrin - Cyhalothrin - Cypermethrin - Deltamethrin - Fenvalerate - Flumethrin - Fluvalinate

treatment for iron toxicity

- Emetic in alert animal, gastric lavage, or gastrotomy (not charcoal) - Fluids, electrolytes, acid/base balance - g.i. protectants (Tagamet, etc) - Chelation therapy... deferoxamine (Desferol®, Ciba) - initial i.v. infusion....15 mg/kg/hr - i.m. 40 mg/kg every 4 -8 hr - continue until serum Fe is below 350 ug/dl (may take 2-3 days) - or is less than the TIBC

bromethalin treatment

- Emetics early - Repeated activated charcoal, saline cathartic (every 12 hr for 6 times; repeated doses should be at half original dose) - Dexamethasone prolongs survival time, but does not reverse syndrome - Mannitol/furosemide for cerebral edema - Diazepam or phenobarbital as needed for seizures - Supportive care; up to 3 weeks for recovery in some cases -PROGNOSIS: VERY GUARDED in mod-severe cases Detox/Symptomatic/Supportive o Emetics early Remember not to give emetics to obtunded animals or those with other conditions predisposing to aspiration o Repeated activated charcoal and saline cathartics every 12 hr x 6 repeated doses should be at half original dose o Steroids (e.g. dexamethasone) are controversial may prolong survival but no change in outcome o Mannitol for cerebral edema o Benzodiazepines or phenobarbital for seizures o Supportive care o May take up to 3 weeks for recovery in some cases

Organophosphates (OP's) and Carbamates sources

- External parasite products...sprays, dips, pour-ons (read the label ! ) - BOTH LARGE AND SMALL ANIMALS - Agricultural ...corn root worm products (i.e. Thimet, Counter, Dyfonate, Furadan) Home / garden insecticides - BOTH LIQUIDS AND GRANULAR organophosphates group is huge; same for carbamates but 100's of unique ones ; mechanism of actions same

diagnosis of pyrethrin/pyrethroid toxicity

- History of exposure - Gen'l lab tests - PMNs; glucose - DDs: OP's, Cl-Hc, metaldehyde, nicotine, strychnine, etc - Chemical analysis - disappointing ...perhaps brain, skin: high concentrations are more suggestive of poisoning

mechanism of type II pyrethrins/pyrethroids

- Membrane depolarization predominates - Affect GABA (inhibitory) channels - *Tendency to weakness, paralysis* -CNS excitement with large amounts

bromethalin lesions

- No gross lesions - Histopath of brain and spinal cord... edema and spongiform change in myelin of brain and spinal cord

lesions of strychnine poisoning

- No reliable lesions in organs - Bait in stomach (dogs rarely vomit with strychnine) - Dye material from bait often obvious - Bruises, hemorrhages from trauma - Signs of terminal anoxia Rapid rigor, rapid relaxation. Cyanosis, possible traumatic evidence of seizures. Birds that died (dunlin and killdeer) exhibited an unusual posture with the wings folded over their back, straightened toes, with their bill in the soil and excreta extruded from their vent.

copper summary

- Occasional acute poisoning - serious GI and hepatic damage - Chronic icterus/hemoglobinuria in sheep - Closely associated with Mo and SO4 - Familial condition in selected K9 breeds - Diagnosis based on C/S, serum Cu, biopsy - Rx is chelation and mineral competition

lead sources for all animals (summary)

- Old paints (pre-1970) - Lead batteries !! - Lead-based paint (chips or dust) - Motor oil from leaded-gas engine (minor) - Old grease (modern lubricants lead free) - Lead weights, fishing sinkers - Lead shot, bullets - Old linoleum - Pollution Sources of lead are many and include o Lead paint chips and dust (large and small animals and humans) Young who are typically mouthing/chewing contaminated surfaces o Lead based motor oil (large animals but greatly reduced with the elimination of lead-based gasoline) o Discarded batteries (large animals) o Toys (small animals and humans) o Lead bullets (wild animals, waterfowl, secondary small animal and humans) o Solder (small animals) o Sinkers (small animals) o Secondary poisonings from consumption of contaminated animals of prey (large and small animals and possibly a significant factor in humans) o Of historical importance, lead pipes, wine vessels and moonshine containers

Chlorinated Hydrocarbon Insecticides source:

- Old products, most off market ( i.e. DDT, chlordane, dieldrin, aldrin, toxaphene) - Very persistent, fat soluble how they get poisoned: - Accidental or intentional - retention of old products that are improperly stored or retained - Except Lindane for lice, most no longer used in US - Environmental contamination from previous use

prevention of chronic copper poisoning in sheep

- Producer + feed supplier education - Evaluate Cu, Mo, S in ration o grain, forages, minerals, water, mineral blocks

lead toxicity clinical signs in horses

- Recurrent laryngeal nerve paralysis results in "roaring" - Ataxia, incoordination - Foals metaphyseal sclerosis

zinc toxicity treatment

- Remove zinc foreign bodies - Symptomatic, supportive, fluids for renal failure - H2 receptor blockers - cimetidine, ranitidine - Chelation o D-penicillamine 110 mg/kg PO divided 6-8h for 5-14 days o CaEDTA - 100 mg/kg divided 4x/day Often good recovery without chelation after removal of zinc item

treatment for sub-acute poisoning

- Simply *wait for Se residues to deplete* - Arsenic containing cpds eg 50 - 100 ppm *arsanilic acid* to aid excretion in calves or pigs -*Remove offending feed*

mechanism of type I pyrethrins/pyrethroids

- Slow the opening and closing of neural sodium and perhaps K+ and chloride channels - This lowers threshold for firing of nerve and extends the action potential - *CNS stimulation, muscle tremors, excitement* not all mechanisms known; this is the hypothesis

amitraz exposure treatment

- With therapeutic doses, no treatment needed - In overdose situations... - bathing for topical exposure - emetics, gastric lavage, or activated charcoal for ingestion - In dogs, *yohimbine* (0.11-0.2 mg/kg IV) reverses bradycardia, depression; repeat as needed (short T1/2) - *Atipamezole* (alpha-2 blocker) (50 ug/kg IM) Fewer side effects than yohimbine - Supportive care

selenium as an essential trace element

- cellular antioxidant (similar to vitamin E) - glutathione reductase, thyroxin formation - related to sulfur - competes with S and can replace sulfur in sulfur amino acids

sub-acute poisoning

- feed additives - in swine Toxic dose: 4 - 20 ppm Se in feed for 2 - 6 weeks Approved...0.3 ppm -posterior and/or anterior *paresis, "hemiparesis"* -necrosis of coronary band, *hoof sloughing*, -*hair loss*, dry, broken, split hair, especially mane & tail ◦ Anterior symmetrical paresis often followed by quadriparesis ◦ Keratinized tissue damage necrosis of coronary band hoof sloughing hair loss dry, broken,split hair, especially mane & tail

diagnosis of bromethalin

- history of exposure - characteristic microscopic lesions in brain and spinal cord - possible hyperglycemia - EEG: spike & wave activity, voltage depression, abnormal Hi voltage Slow Wave typical of cerebral edema - chemical detection of bromethalin in tissues (brain, fat, liver, kidney) at selected labs History of exposure Possible hyperglycemia or electrolyte imbalances (these may be secondary to stress or dehydration, however) EEG: o spike & wave activity o voltage depression o abnormal high voltage slow wave typical of cerebral edema Pathological Findings o chemical detection of bromethalin in tissues (brain, fat, liver, kidney) at selected labs o edema and spongiform change in myelinated tissues of brain and spinal cord

acute selenium poisoning

- injectable products...lambs, pigs, calves - Narrow margin of safety Therapy: Young - 0.05 mg Se/kg bwt Adult - 0.1 Toxic: (mg/kg BW) Lambs - 0.4, pigs - 1, calves - 1.2 Clinical signs - onset within 12 - 48 hr after injection - slow to *labored breathing to gasping for air* - *convulsive spasms, respiratory failure, death* ◦ 2 ̊ injection onset within 12 - 48 hr after injection slow shallow to labored breathing to gasping for air respiratory failure convulsive spasms Sheep may show just depression and sudden death ◦ 2 ̊ oral exposure acute gastroenteritis diarrhea shock

lead sources for large animals

- lead batteries !! ...access to junk - Discarded/ignored batteries freeze, breakexpose plates - lead-based paint • Motor oil from leaded-gas engines; highly absorbtive - Dramatically reduced by unleaded gasoline

lead sources for small animals

- lead-based paint (chips or dust) - lead weights, fishing sinkers - lead shot, bullets - lead solder - lead toys

pyrethrins - pyrethroids toxicity

- most quite safe, not very toxic (100 - 2000 mg/kg BW orally) but occasional cases in individual cats - *Toxicity enhanced by synergists*(depress MFOs which metabolize these compounds--makes them more efficacious) - oral toxicity is very low - destroyed in gut -Exposure is through skin or by inhalation - use of dog products on cats... - permethrin (Type I) has high risk to cats

pyrethrin/pyrethroids clinical signs

- onset often <1 hr - hyper excitable, tremors, seizures, ataxia, vomiting - some products (Type II) include more salivation (can alleviate by giving treat), weakness, abnormal posture - clinical poisoning usually goes to recovery (rarely death) in 24 - 72 hrs - topical allergic pruritis, hyperemia, urticaria, dermatitis not uncommon

Source of pyrethrins/pyrethroids

- quick knock down fly sprays - premise fly control products - many dips, spot-ons, sprays, shampoos, ear tags, crop sprays - Ready to use generally < 2% a. i. - Spot-on products 40-65% concentration

Pyrethroids

- synthetics, stable - permethrin, cypermethrin, fenvalerate, etc. -very light sensitive -more stable than natural pyrethrins

Avicides: 4-Aminopyridine (Avitrol®)

- used in feedlots to keep birds away - 0.5 - 3% in grain baits - restricted use - enhances ACh release at synapses, esp. neuromuscular jnct - birds become disoriented, emit distress cries, drive others away

OP Note: chlorpyrifos Dursban, Lorsban : intermediate syndrome ; cats/exotic breed cattle

- very sensitive (poor metabolism); protracted course - not labeled for cats - signs: delayed 1 - 5 days muscle tremors, ataxia, seizures, depression, anorexia may persist 2 - 4 weeks - treatment: long term supportive care - atropine to effect, 2-PAM, charcoal - bathe to stop absorption from skin "exotic" breed cattle... ..delayed (10 - 14 d) effect of pour-on • often anorexia, weight loss • some show salivation and other acute OP signs • treat with 2-PAM, oral charcoal • Bulls more susceptible - associated with testosterone promotion of oxonation difficult to treat compared to first syndrome; best you can do is give atropine and hope it will work intermediate syndrome: will occur despite first treatment (not well understood though)

diagnosis of chronic copper poisoning in sheep

-* History, clinical signs* - Laboratory testing Liver >150 ppm Cu (wwt), Kidney > 15 ppm Cu (wwt) Blood > 1.5 ppm CU *Cu and Mo in feed*, other ration parts (remember timing) *Cu from all sources is additive*

mechanism of nicotine

-* Mimics* action of *acetylcholine* at cholinergic synapses in muscles, autonomic ganglia, and CNS • small doses stimulate CNS • large doses depolarizing paralysis • *death from respiratory paralysis*/muscle paralysis

fluoride sources

-*water and plants* -mineral deposits-effluent, tailings -pesticides -product of industrial processing of *aluminum ores or phosphate* fertilizers *fertilizers and calcium/phospahte minerals must be defluorinated -past history: aerial contamination from aluminum smelters and steel mills -more likely to see than thallium or Hg poisoning

acute fluoride toxicosis

-14 cattle on a Kansas pasture died from ingestion of a wood preservative compound containing *sodium fluoride* and copper naphthenate -clinical signs included: *depression, anorexia, ataxia, diarrhea and recumbency*

zinc toxicity levels

-Ferrets: 500 - 1,500 ppm ora-->ldiffuse nephrosis-->3,000 ppm lethal -Guinea pig: oral LD50 (zinc chloride) 96 mg/kg -Rats, pigs, and poultry tolerate 1,000 to 2,000 ppm dietary zinc without adverse effects -Decreased feed consumption in cattle and sheep fed > 1,000 ppm zinc

Molybdenum pathogenesis

-Molybdenum is a *copper antagnoist*, mainly a clinical problem in cattle exposed to excess Mo -Molybdenum promotes copper excretion via formation of a copper-molybdate complexes, thus antagonizes accumulation of Cu; the result of excess of Mo in cattle is *copper deficiency*

thallium treatment

-Prussian blue (Potassium ferricyanide) -Dithizon..chelator for thallium; contraindicated in cats for some reason. seem to be sensitive to it. if have to use it, use lower dosage than other animal species. -ineffective once clinical signs show

mechanism of anticoagulants

-Vitamin K1 is regenerated by reduction by Vitamin K1 epoxide reductase -anticoagulants block recycling of vitamin K from epoxide to reduced form -interfere with vitamin K utilization by blocking synthesis (carboxylation) of vitamin K dependent clotting factors (esp. VII, IX, X) -factor VII (PT) affected early; factor IX (PTT) Later -clotting factors have different half-lives; those with shortest half life disappear first (factor 7 followed by factor 9). Can be deciphered by tests done in clinic. Get prolonged prothrombin or PTT time. -not until you get depletion of factor 9 that you get bleeding -active form of vitamin K1 is vitamin KH2 (hydroquinone) -when you have anticoagulant rodenticides, inhibit vitamin K epoxide reductase -vitamin K is stuck in position and can't recycle so whatever is activated will be depleted then animal starts to bleed

species affected by copper

-all species -*sheep* most t risk -across all species accumulation may be *primary-metabolic* or *secondary cholesetatic*

sources of mercury

-batteries (discontinued in USA in 1996); some disc batteries contain mercury oxide=small risk) -some pharmaceuticals: calomel -also industrial effluents, sewage sludge, ocean waters -marine fish/shell fish on top of food chain (mackerel, shark, swordfish, tilefish); owners who feed cats fish -Tuna moderate -elemental mercury: barometers, thermometers, fluorescent tubes

Lead battery cattle cased

-battery fragments observed in feed bunks; tractor battery ground in with ration -onset of clinical signs 2 days post exposure: ataxia, blindness-->running into fences, tremors, seizure like activity, head-pressing, death -58 to 60% of a battery weight is lead -50 lb battery contains 30 lb of lead -acute toxic as low as 50 mg/kg body weight -acidic environment or ration can cause lead to become more toxic -dead livestock cannot be rendered

mechanism of mercury toxicity

-binds to sulfhydryl groups and *inhbiits enzymes and protein synthesis* -*inhibits mitochondrial function* by binding to alpha-lipoid acid (Thioctic acid): *sulfur-containig organic acid cofactor involved in aerobic metabolism pyruvate dehydrogenase complex -similar mechanism to arsenic

mercury public health concerns

-bioaccumulation and biomagnification in food chain -sediments-->fish-->mammals, including humans -Hg residues in kidney and muscle tissue, currently most concern in fish -higher concentrations range from 0.7-1.5 ppm

environmental impact/food safety impact of fluoride

-cattle, horses, wild herbivores -food safety not significant concern

the total knowledge of poisons include

-chemical properties -identification -biological effects -treatment of disease caused by the poison -*note that toxicology is a "borrowing specialty" borrowing heavily from other sciences and medicine*

the veterinary toxicologist deals with

-chemicals -feed additives -environmental contaminantss -pesticides -natural toxins of plant and animal origin all which may adversely affect the health of animals

treatment for Mo toxicity

-copper glycerinate infection (60 mg SC for calves ;120 mg SC for adults -dietary Cu sulfate to provide 1 g daily per adult cow (0.5 kg in 50 kg salt) or 10 kg Cu sulfate per ton of grain, fed at 0.1 kg/cow/day

delayed clinical signs of anticoagulants due to

-depletion time for active vitamin K -half life of K dependent clotting factors (VII @ 6.2; IX @ 13.9 hr; X @ 16.5 hr) -Clinical coagulopathy usually from 3-6 days post ingestion *As short as 36 hr (dosage dependent) -PT drops first; PTT later

clinical effects of Mo toxicity

-early intractable diarrhea, greenish bubbly diarrhea after 1-2 weeks of exposure -decreased milk production or slowed growth -reduced libido on bulls and infertility in cattle (Achromotrichia--fading of hair color) due to Cu deficiency and reduced melanin production--bespectacled -joint pain, lameness, spontaneous fractures, anemia, pica

mercury toxicity

-elemental Hg low in toxicity orally -Hg salts: ca. 1 mg/kg/d toxic to cats in 15 days -Hg salts: large animals-8 to 12 mg/kg -Methyl (alkyl) mercury 0.2-0.5 mg/kg -Phenyl (aryl) mercury (swine) about 1 mg/kg -overall *Highly toxic on chronic basis*

lesions from acute fluoride poisoning

-grossly visible lesions include perirenal edema, pale *kidneys*, and *fore stomach ulceration* -all 3 cows had extensive *renal cortical* tubular *necrosis* -these findings indicated that the sodium fluoride caused renal tubular necrosis leading to renal failure -copper ndphthenate may have contributed to abomasa ulceration; but was not appreciably absorbed from the GI tract

thallium basics

-heavy metal: toxic and highly cumulative -rodenticide..1920's to 1960's -tasteless, odorless, easily masked in baits -once used as a depilitory -off market since 1965 -occasional exposure from old products, cleanup of buildings, etc.

diagnosis of fluoride toxicosis

-history: exposure to feeds, environment -clinical signs; lameness, weight loss, elongated hooves, lapping water -lesions: dental fluorosis in erupting teeth; exostosis of limbs, ribs, mandible -F analysis: urine (15-20 ppm, recent), bone (rib-prolonged exposure >3000 ppm) -feed, water (current risk) -need to be consistent with bone you are using; coccygeal bones common

the toxicologist may have training in

-human medicine -pharmacology -physiology -pathology -chemistry -the integration of these areas of knowledge is applied toward solving practical problems

current toxicology practice challenges

-larger, more sophisticated clientele -fewer obvious acute classical toxicoses -emphasis on vague and subtle response to animal production environment -food safety issues (antibiotics, genetic-based products, environmental contaminants) -nutritional toxicology questions -immune function effects--increased disease -geentic manipulations (of crops) and new energy technologies--new questions

20th century toxicology

-metals (As, Hg, Pb, TI)-->generally banned -DDT, chlorinated pesticides-->residues -stilbesterol, estrogens-->fetal and environmental -Thalidomide-->FDA regulation-->preventive -PCBs-->toxicity, residues -TCDD (dioxins): Vietnam, Love Canal, Times Beach -feed additives: metals, ionophores, antibiotics, arsenicals, hormones -mycotoxins: AFB1, T-2, DON, FB1 -bioengerineering: BST; Bt corn-->accepted? -biofuels economy: bioethanol/biodiesel byproducts-->mycotoxins, hydrogen sulfide -food contaminants: melamine, etc.

fluoride affects

-mineralized tissues such as teeth and bone -deposited in hydroxyapatite crystal of bone and distorts normal Haversian system remodeling -dental fluorosis is dystrophic formation of dentin and enamel in erupting teeth only (marker for time of exposure) -affects teeth that are erupting, not already erupted -attrition can only occur during teeth growth -can have bone abnormalities without tooth abnormalities

clinical effects of thallium

-multisystemic 1. *GI necrosis*: similar to arsenic, severe hemorrhagic gastritis, congested oral mucosa (don't know why) ; lesions start around commissure of lips--cracking etc. 2. *neurologic*: trembling, motor paralysis, mental retardation 3. alopecia and skin sloughing (chronic) form 7 days to 2-3 weeks after ingestion; see in subacute or chronic cases ; due to damage of hair follicles. single exposure will lead to loss of hair. * Renal and liver injury (subacute/chronic)

agent

-poison/toxicant -chemical (generic, chemical origin) -xenobiotic (any foreign compound) -toxin (biological origin) -elements -pharmaceuticals -nutrients

factors affecting poisoning outcome: health status

-pre-existing diseases -immune status -clinical illness -biological variation • Pre-existing diseases ○ Across spectrum: infectious diseases, viral, bacterial, fungal, etc. • Parasite infestation causes breakage in skin allowing more absorption of toxicants • Animals need to be vaccinated; well vaccinated animals more resistant to intoxications because any disease likely increases susceptibility of animal to intoxication

characteristics and limitations of the LD50

-quantal (all or none) response of a group -straight line on semiology or prohibit paper -lethal to 50% of animals by defined conditions -does not address severity/clinical characteristics -no

Top 10 ISU VDL Toxic Dx: next 33% all cases

-salt/water (swine) -ionophores (ovine/equine/canine) -OPs (K9/bovine/porcine/avian) -urea/NPN (bovine) -idiopathic (Crv/ovine/equine/canine/feline) -yew (bovine/ovine) -zinc (canine)

Response

-what? clinical, performance, lesions, etc.; death, convulsions, poor performance, carcinogen, infertility (good vs bad; complete vs graded; reversible?) ; • Organophosphates response: SLUDD • Much depends on target organs, molecular effects, etc. • Carcinogens: takes long time for cancer to manifest so it's hard to say what the cause is of cancer • Some responses can be beneficial like chemotherapeutics ○ They are really toxins that target specific cells • Some responses are complete or graded ○ Complete: acute death ○ Graded: increased severity of a disease process Some reversible, some not -where? defined organ system (s); local, systemic, characteristic effects on body systems (key to systematic diagnosis); many toxicants, few body systems -when? recent, delayed, acute, chronic -why? sources, animal/chem factors; accidental/unintended exposure, overdose of intended product, drug/toxicant/nutrient interaction, animal or environmental interaction, malicious poisoning ; • Response determined by the animal and the direction of the animal in the environment • Every individual has different susceptibility because genetic makeup, age • Some young animals don't have developed systems, blood brain barrier • Pregannt animals, undernourished animals effect response of particular animal • When animal exposed to lethal dose, certain population dying because of genetic factors, how malnourished animal is, etc. • Environmental factors: ergot alkaloids target? ○ In summer with a lot of heat, may have heat intolerance ○ In winter, vasoconstriction, exposed to ergot alkaloids-->necrosis Sublethal concentrations -how? access, route, mechanism of action (pathogenesis); attack common receptors, compete for metabolites, damage membranes, alter nucleic acid synthesis ; • LED50 derived in labs and well-defined conditions with uniform species of certain age (6-8 weeks) • In real world, animals of all ages, different conditions, etc. so LED50 needs to be considered with caution • Response also depends on mechanism of action ○ How is this toxicant causing these clinical effects • What organs affected • Some toxicants cause oxidative stress • Some interfere with nutrition and metabolism • All factors effect response • Dose-response relationship depends on target and number of factors

mercury diagnosis

-whole blood in EDTA (>1 ppm) -liver -kidney; primary target organ to Proxima tubular epithelial necrosis. -hair; good for live animals; good for chronic exposure cases -urine -feeds acts like arsenic organic forms penetrate BBB; earliest clinical signs you see are those of neurological involvement, ataxia, cats vocalizing a lot. first clinical signs seen in cats in the 50's.

animals susceptible to chlorinated hydrocarbons

....All (cats, cattle, swine, wildlife) - Acute poisoning - Residues - cats especially sensitive

source of bromethalin

....Assault (Purina), Vengeance, Trounce, Wipe- Out, Nail-A-Rodent, Fastrac, Top Gun, Clout All-Weather Bait (14 g blocks) As 0.01% bait, usually green pellets Place packs...16 to 42.5 g of bait don't assume just one intoxicant in a bait

areas of high molybdenum in the USA

Florida, Oregon, California, some parts of Nevada

specimens from dead animals

Heart blood Stomach/crop contents Liver-- Unfixed and fixed Kidney-- Unfixed and fixed Peri-renal fat Skin/hair Entire brain - Make a sagittal section of the brain; Freeze one half and fix other Bile

diagnostics for anticoagulant toxicity

History and physical exam! o Hemorrhagic syndrome present Clotting time prolonged Elevated prothrombin time (PT) 2-3 days post exposure o Activated partial thromboplastin time (PTT) 3-5 days post exposure o PIVKA - Proteins Induced by Vit K Antagonists (a.k.a. Thrombotest®) detects precursor proteins of clotting factors o Detection of active ingredient in liver, blood, bait o Value of assay in stomach contents?? Pathological Findings o Lesions: if it can bleed it probably will hemorrhages, hematomas, hemothorax hemarthrosis; subdural hematomas occur in a variety of tissues, organs, spaces reflect failure of prothrombin based clotting • platelet function normal

mechanism of action of metaldehyde

Hydrolysis to acetaldehyde - unlikely ? Reduced brain Na, 5-HT and 5-HIA Low Na & 5HT seizure threshold Increased monoamine oxidase activity Decrease in brain GABA reduced GABA seizures Hyperthermia prominen Metaldehyde interferes with GABAergic system function MAO activity is increased while norepinephrine, 5-HT and 5-HIA are decreased low NA and 5-HT lower the seizure threshold o Older studies postulated that hydrolysis to acetaldehyde was responsible for the toxic effects but recent studies do not support this. metaldehyde may have direct toxic effects

zinc phosphide mechanism

Hydrolyzed in stomach; enhanced by full stomach with release of gastric acid H+ • Zn3P2 → PH3 (phosphine gas) + Zn+2 H2O MECHANISM • *PH3 ...blocks cytochrome oxidase* and membrane ion transport (myocardium) • Zn moiety ...strong *emetic* (may be protective to dogs, rats cannot vomit)

lead chelation treatment

Increase excretion - *chelators* • *CaEDTA* - IV, SQ (standard Rx for cattle; availability limited) • *D-penicillamine - oral* in SA • *Succimer* (DMSA , dimercaptosuccinic acid) (Chemet, Bock) - *oral* in SA - Recently approved (dogs) 10 mg/kg TID for 5 days, then BID for 2 weeks - Effective in cattle, but dosage and expense preclude o CaEDTA - IV, SQ Standard Rx for cattle: 110 mg/kg divided b.i.d. with initial IV and half of dosage SQ; continue for 3-5 days then rest for 3-5 days to prevent excess chelation of essential metals. Availability limited only from chemical companies. May promote lead absorption, so clear gut of lead if possible before starting therapy. o D-penicillamine - oral in Small Animals (clear gut of lead first) o Succimer (DMSA , dimercaptosuccinic acid) (Chemet, Bock) - oral in SA o Recently approved (dogs) 10 mg/kg TID for 5 days, then BID for 2 weeks lead still in gut) (OK with o Effective in cattle, but dosage and expense preclude use except for very valuable animals

mechanism of retenone

Inhibit electron transport; Interferes with ATP synthesis • Toxicity enhanced by combination with pyrethrins/pyrethroids; may be dealing with combo of intoxicants in one exposure • Acute oral LD50 300 mg/kg in dogsvomiting, lethargy, dyspnea, tremors-seizures + hypoglycemia • Cats mores sensitive than dogs not very potent alone need to ingest a lot see CNS excitation animals will have tremors, seizures, hypoglycemia

Absorption, Distribution, Metabolism and Excretion (ADME) of strychnine

Ionized in acid medium (pk1 = 6.0, pk2 = 11.7) and therefore absorbed in small intestine, but absorption is rap Metabolism of parent compound in liver; metabolites excreted in urine. Highest tissue concentrations occur in blood, liver, and kidney. Does not concentrate in nervous tissues. At death, the highest concentrations are usually present in stomach contents.

Convert lbs/ton in feed to percentage and % to ppm

Issue: Feed ingredients often stated in lbs. per ton or grams per ton; tox data in ppm. • Convert to a ratio e.g. 1 lb/2000 lb • = 0.0005 (fractional part of 1 lb in 1 Ton) • = fraction x 100 = % = 0.05% • Remember: to convert % to ppm multiply by 10,000 (ie move decimal 4 places right) therefore 0.05% =500 ppm • Convert 500 ppm back to % by moving decimal 4 places left (500 ppm = 0.05%)

4-Aminopyridine (Avitrol®) toxicity

LD50: rat 20 mg/kg bwt mouse 10 dog 3.7 horse 3 (lethal) also cattle, zoo animals, deer, waterfowl

differential diagnosis for chronic copper toxicity in sheep

List other signs or toxicities that may be confused with this condition and important findings that are useful in differentiating other conditions from the one under discussion. If necessary, utilize species/breed subheadings

treatment of cholecalciferol

Medical Emergency!! ...varies according to progression of disease 1. Soon after ingestion...emetics, cathartics, activated charcoal (0.5 - 1 g/kg t.i.d.) ASAP!! -continue 1-2 days to block enterohepatic cycling 2. Saline diuresis...physiologic saline (0.9%) given at 2 - 3 X maintenanceCa loss 3. Furosemide...5 mg/kg IV, followed by 2.5 mg/kg orally t.i.d or b.i.d. 4. Prednisone...2 -3 mg/kg orally s.i.d or b.i.d. (block osteoclast activation, GI & renal uptake) 5. Calcitonin...4 - 6 IU/kg SQ @ 2-3 hrs initially - serum Ca levels reassessed 2 - 3 hrs after dosing 6. Biphosphonates (Pamidronate) = inhibit bone resorption, by IV saline infusion @ 1.3 - 2 mg/kg over 2hrs. Repeat in 4 days (long lasting effect) (expensive) 7. Ca restriction, antiemetics, GI protectants - Prognosis guarded - may die 2-5 days post exposure - Prolonged Rx, up to 4 weeks may be needed - Treated on an outpatient basis after serum Ca stabilizes

treatment of vitamin D toxicity

Medical Emergency!! ...varies according to progression of disease o Soon after ingestion...emetics, cathartics, activated charcoal (0.5 - 1 g/kg t.i.d.) ASAP!! Continue 1-2 days to block enterohepatic cycling o Saline diuresis...physiologic saline (0.9%) given at 2 - 3 X maintenance promotes Ca++ loss o Furosemide...5 mg/kg IV, followed by 2.5 mg/kg orally t.i.d or b.i.d. o Prednisone...2 -3 mg/kg orally s.i.d or b.i.d blocks osteoclast activation, GI & renal uptake o Calcitonin...4 - 6 IU/kg SQ @ 2-3 hrs initially serum Ca++ levels reassessed 2 - 3 hrs after dosing o Biphosphonates (Pamidronate) given by IV saline infusion @ 1.3 - 2 mg/kg over 2hrs repeat in 4 days (long lasting effect but expensive) o Ca++ restriction, antiemetics, GI protectants PROGNOSIS o Prolonged Rx, up to 4 weeks may be needed ++ o Treated on an outpatient basis after serum Ca stabilizes

growth regulators

Methoprene Lufenuron

toxicity of nicotine

Minimum lethal oral dosage in dogs and cats = 2-3 mg/kg • Minimum lethal dose IM lower ~ 1 mg/kg • Alkaloid - Ionized in acid medium which slows absorption from stomach also toxic to cattle and horses

source of metaldehyde

Molluscacide - control snails, slugs (Gulf coast, Pacific NW, moist areas) baits often 3 - 5% metaldehyde seasonal (gardening time) dogs develop taste for bait may also contain an OP or Carbamates grain-based, pellets, liquids, powders solid fuel (camp stoves) When in moist areas these can release metaldehyde for up to 10 days Concentrations in the United States are usually 1.5-5% (generally 3-5%) metaldehyde o European baits contain up to 50% metaldehyde Also used as fuel for camping stoves, lamps, etc. Color flame tablets that are used for entertainment contain metaldehyde Dogs in particular are prone to intoxication as some products are flavored (molasses, etc.) o Flavoring less common now due to regulatory requirements intended to decrease unintentional poisoning A relatively common poisoning in dogs, horses, humans and livestock (cats are pickier about what they eat!) May contain organophosphates or carbamates as well pellets, liquids, powders, granules and grain-based formulations o Ortho Bug-Geta Snail and Slug Killer®, Ortho Metaldehyde 4% Bait®, Slug Pellets®, Slug-Tox®, Antimitace®, Deadline®, Snarol®

treatment for chronic selenium poisoning

No good treatment available. Focus on prevention! • Terminate exposure • Primarily supportive • Low Se and high sulfur diet

Convert Food or Feed Concentration to mg/Kg BW dosage in Animal

Often exposure in feed is expressed as a concentration, but toxicity to animals is on a body weight basis • To convert feed concentration to BW dosage must know or estimate: - Concentration in the feed or food - Approximate weight of animal at risk - Amount of food consumed or an estimate of food consumption as % of BW • Remember 1 ppm = 1 mg/kg • Assume 1000 ppm in feed - 1000 ppm in feed = 1000 mg/kg of diet • mg toxicant in feed x amount feed eaten in kg = mg consumed by animal IF 100 kg animal consumes 1 kg feed, then 1 kg x 1000 mg/kg = 1000 mg (of toxicant) eaten • 1000 mg/kg x 1 kg = mg toxicant /kg BW 100 kg BW = 10 mg/kg BW • IF our 100 kg animal consumes 2 KG feed, then 2 kg x 1000 ppm = 2000 mg eaten • 1000 mg/kg x 2 kg = mg/kg BW eaten 100 kg BW = 20 mg/kg BW Thus, increasing relative consumption of feed increases dosage in a predictable manner...

Organothiophosphates have

P=S group; have to be activated; have to be disulfurated and replaced with oxygen at sulfa group more stable in the environment bromethalin: increased toxicity via metabolism in attempt to excrete

wood preservative "penta" (restricted use) (can use as utility poles, fence posts, marine wood) well absorbed ended up with residues in milk

Pentachlorophenol

ddx for vitamin D toxicity

Primary renal failure, hypoadrenocorticism, primary hyperparathyroidism, hypercalcemia of malignancy, feline idiopathic hypercalcemia

*analytical toxicology tests*

Put results in proper perspective: *Relate to clinical signs* *Only rarely* do numbers mean anything by themselves.

lead poisoning signalment

Seasonal incidence: *spring*, early summer • Age: often younger animals (pups, calves) • Location: - Dogs: older, lower income areas, work places - Cattle: "casual" management, old buildings, junk piles • Species: *dogs, cattle* most frequently

fungicides

Seed protectants - animals exposed by consuming treated seed captan: long used on seed corn; presents a low risk of poisoning -newer products: metalaxyl (Allegiance), mefenoxam (Apron), fludioxonil (Maxim) also low toxicity

mechanism of cholecalciferol

Systemic Toxicant • Cholecalciferol renal 1, 25-dihydroxyvitamin D • In intoxications, 25 hydroxy D3 is a mediator as well • Increase in serum Ca levels by ... 1. increasing Ca (and P) absorption from gut 2. via PTH - increase osteoclast bone resorption 3. renal retention of Ca via distal tubule resorption both are active in terms of intoxication

Hemodialysis: *(direct removal of the toxicant and/or metabolites from circulation)*

This is more effective than peritoneal dialysis. Blood is pumped from one catheter, through the dialysis unit over a semipermeable membrane, and back through a second catheter for 6-8 hours. The toxicant diffuses across the semipermeable membrane into the dialysis solution based on differences in osmotic and concentration gradients.

Hemoperfusion:

This is significantly more effective than hemodialysis and peritoneal dialysis. Blood is passed directly over an adsorbing material such as activated charcoal. Recommended for lipid soluble substances Down side-- Thrombocytopenia, hypocalcaemia

peritoneal Dialysis:

This utilizes similar principles as for hemodialysis. It is the most easily performed dialysis procedure and is also associated with lower risk of complications. However it is the least effective of all dialysis procedures.

exposure to paraquat from

Toxicity from agricultural application is unlikely. Livestock: *consumption of concentrates or tank mixes.*

relatively nontoxic to ruminants (Scotts Weed 'N Feed).

Triazines (Atrazine) an herbicide

Receptor antagonists/blockers:

Two chemicals bind to the same receptor and produce less of an effect when given together. E.g.. Naloxone Vs morphine and other narcotics; Atropine Vs organophosphorous or carbamate pesticides.

sources of dinitro compounds (herbicides)

Used in *herbicide, fungicides, and antiparasitic agents*. *2,4-dinitrophenol (DNP)* 2.4-dinitro-ortho-cresol (DNOC) 2-sec-butyl-4,6-dinitrophenol (DINOSEB) Dinitro®, Basanite®, Dow General Weed Killer®,

clinical signs of cholecalciferol intoxication

Usually begin 12 - 36 hours after ingestion • initially anorexia, vomiting (occasionally bloody), depression, muscle weakness • cardiac and renal changes as toxicosis progresses • bradycardia & heart failure may develop • hypertension, polyuria, polydypsia

Mechanism of Action of anticoagulants

Vitamin K-dependent clotting factors Factor VII (extrinsic pathway), factor IX (intrinsic pathway), and factors X and II (prothrombin) (common pathway). o Clotting factors synthesized in the liver VitaminKanessentialcofactorforcarboxylationofacarboxycoagulation proteins (the functional form) Vitamin K metabolism is tightly conserved in the liver o Vitamin K epoxide reductase essential for continued synthesis of new factors VII, IX, X and prothrombin Anti-coagulant rodenticides (e.g. dicumarol, warfarin) tie up this enzyme preventing recycling of vitamin K and depleting liver of active, reduced form of vitamin K o However, factors VII, IX, X, or prothrombin already in the bloodstream (synthesized before the ingestion) are not affected and can participate in the normal clotting mechanism o Hemorrhage occurs when viable vitamin K-dependent clotting factors are depleted (thus the usual 3 to 5-day "lag" time between a toxic dose of an anticoagulant and clinical signs) o Factor VII t1/2 shortest (6.2 hours), so the extrinsic pathway shuts down first. Hemostasis is impaired slightly mild degree of hemorrhage may occur Other pathway (intrinsic) still operational and serves as a sort of "back-up." Lab values reflect defunct extrinsic pathway: elevated prothrombin time (PT). o When factor IX is depleted (half-life 13.9 hours), the intrisic pathway (back-up) shuts down and hemorrhage goes unchecked First signs of observable clinical abnormalities are noted and an elevated partial thromboplastin time (PTT or APTT) occurs. PT is still elevated and deterioration of the patient due to hemorrhage may be quite rapid

medications for rodenticide toxicity

Vitamin K1: Oraldosingwithfattymealpreferred improved bioavailability decreased risk of inducing hemorrhage HOWEVER, may be contraindicated if severely depressed, activated charcoal administered or severe GI hemorrhage or vomiting Subq and IM can be used if necessary but use smallest gauge needle possible and switch to oral as soon as possible IV administration strongly discouraged reported anaphylaxis poor bioavailability 3-5mg/kg/d warfarin x 10 days brodifacoum x 2-4 weeks 5 mg/kg/d for diphacinone x 3-4 weeks Horses 2mg/kg/d maximum VitK3(menadione)isineffective Time lag 3 - 6+ hrs for effective coagulation so will need blood products for immediate coagulation o Blood or plasma transfusion immediate clotting factors fresh whole blood or FFP use with crystalloids for volume expansion (FFP not an effective volume expander) o May need to sedate to prevent further injury-AVOID phenothiazines (ACE)

• An owner is bringing Fluffy the cat in the day after she brought her dog Frank into the clinic for an annual examination • Owner called and says Fluffy is acting odd • Driving to the clinic now • Owner says that she was out of Fluffy's flea medication She placed a dose of Frank's flea preventative on Fluffy *Exam and treatment: • Fluffy is exhibiting the signs that you suspected • The owner is worried and asks you if there's anything that can be done • Fluffy recovers and goes home • You have a discussion with the owner about future situations

What are the likely clinical signs that Fluffy could be experiencing in this situation? ataxia, tremors, seizures Which of the following drugs would not be acceptable in this case to stabalize Fluffy? atropine You also decide to apply ________ to Fluffy due to ________ caused by the tremors and seizures. - cool packs, hyperthermia If this happens again, what is the first thing that should be done after accidental exposure? wash with soap and water?

Case 2 History and signalment • Owners came home after shopping for several hours only to find out "Bruce", their young black lab is not himself and is wobbling around • Owners remember that the local exterminator was working around the neighbors yard the other day • They call you to ask if they should bring Bruce in as it's late and they can bring him in tomorrow Exam • On presentation Bruce is still ataxic but otherwise appears healthy • He urinated just fine on the clinic lawn before coming in • You draw some blood and serum from to have a quick look to see if anything is off • Owners contacted the exterminator and find out that he had used rampage • Active ingredient = cholecalciferol Results: • No mineralization observed

What should owners be told? This is a possible medical emergency. He should be brought in right now. While you wait for the serum and CBC results, what can be done at this point and why? Administer activated charcoal. The likely cause of the signs is cholecalciferol. What would you expect the serum chemistry levels to show? increased Ca, increased P The serum Ca and P come back with values of 10 and 8.5 respectively. Is there concern for soft tissue mineralization?Yes What diagnostic procedure can be used to help verify mineralization?

clinical signs of canine copper storage disease

Young dogs (6 years of age and younger) may exhibit acute signs (uncommon) o Anorexia o Vomiting o Weakness o Lethargy o Dehydration o Polyuria, polydipsia, icterus, bleeding +, coagulopathy o Older dogs usually show subacute or chronic signs of liver disease

chemical antagonism

a chemical reaction between two compounds produces a less effect e.g.. Chelator dimercaprol (BAL) chelates arsenic, mercury, lead; or antitoxins for treatment of toxins/venoms

Metaldehyde

a molluscacide used to kill snails and slugs o Used in household gardens and other horticultural areas prone to molluscs o Seasonal (spring) o Moist geographical areas (e.g. Gulf Coast, Pacific NW)

As shown, accurate calculations require reasonable estimates of feed intake.

a. Feed intake varies widely among various species and sizes and ages of animals and according to exercise, ambient temperature, and specific conditions such as lactation and pregnancy. b. Estimates of the average amount of feed consumed by common domestic animals during various stages of the life cycle are published by the National Academy of Sciences, National Research Council c. Toxicity may vary if feed or water is consumed quickly at one time, rather than evenly throughout the day. (1) Slower intake allows metabolic detoxification and excretion and usually increases tolerance to acute poisoning. (2) Conversely, toxicants may accumulate in the body from dosages provided daily in the feed. d. Average water intake values (by weight) for various animals are approximately twice the amount of feed consumed. (1) Water consumption varies widely, depending on weather, exercise, health status, palatability, and other variables. (2) Any estimate of the role of water in toxic exposure must be done with these environmental and physiological factors in mind.

*Enhancing Elimination of Toxicants/Metabolites* that are already absorbed

a. anion exchange resins b. increased rate of excretion: forced diuresis via fluid therapy, *ion trapping*, Direct removal of the toxicant and/or metabolites from circulation

where is Mo in excess in soil?

acidic, wet poorly drained soils

warfarin

an effective treatment for human thrombotic disorders as well as being a previously effective rodenticide (resistance common now) Warfarin and similar compounds diphacinone (Tomcat®, Ramik®, Mousemaze®) and chlorophacinone (Rozol®) are first generation products now infrequently used as rodenticides due to rodent resistance, especially to Warfarin. usually formulated as 0.05% compounds

4-Aminopyridine (Avitrol®) diagnosis

analysis of stomach content, vomitus, liver, bait

lesions of molybdenum toxicity

anemia, enteritis, osteoporosis, hemosiderosis

most commonly used rodenticides

anticoagulants

why are rodenticides dangerous

because they are designed to be both attractive to and lethal to mammals

diagnosis of selenium poisoning-sub-acute

bilateral polio-malacia of spinal cord - measure Se in feed (> 4 ppm), -measure Se in liver (> 3 ppm) bilateral poliomyelomalacia of spinal cord, especially cervical and thoracic cord measure Se in feed, liver

Which of the following statements is true about chlorinated hydrocarbon pesticides?

can be absorbed trandermally

amitraz products should not be used on

cats

the ratio of the acute to chronic LD50 doses is the

chronicity factor ; compounds with cumulative effects have a higher chronicity factor -a chronicity factor greater than 2.0 indicates a relatively cumulative toxicant • Some compounds take less of a compound to cause a sudden response if given over several days • Some compounds easily metabolized and some not • In general compounds not easily metabolized tend to have higher chronicity factor as opposed to compounds easily metabolized • Caffeine: metabolized quickly • Warfarin: anticoagulant rodenticide ○ LD50 § If want to kill 50% of mice, give 1.6/bw § If give over 90 days, need to give much less because not easily metabolized or excreted and it is cumulative • Difference between dose and dosage: ○ Dose is a total amount • If given in small dosages over long period, get cumulative effects • Could have build up effect on target Target not easily regenerated

expressions of safety for drugs are given by

comparisons of the LD50 to the ED50

wood pesservative ;a coal by-product (restricted use now) (railroad ties) absorbed through skin caused hepatic necrosis caused food residues being passed in milk so phased out high efficacy

creosote

Aryl Hydrocarbon Lindane

cyclic ring

toxicosis

describes the *disease that results from exposure to a toxin.* The term toxicosis is often used interchangeably with the terms poisoning and intoxication -"arsenic *toxicosis* is characterized by acute onset of vomiting and fluid to hemorrhagic diarrhea"

OP =

different molecular structures; not all uniform. aliphatic, cyclic or heterocyclic esters of phosphoric acid; all esters of phosphoric acid have P=O bond adjacent to the ester; oxygen bonded are immediately available for action; don't need to be activated or metabolized to toxic compound so works sooner

Dispositional antidotes:

diminishes the concentration of toxicant at target sites by changing absorption, biotransformation, or excretion of the toxicant. E.g.. use of emetics, activated charcoal. any drug that effects absorption enhance excretion of toxicant

discovery of anticoagulants

discovered in the 1930's when *dicumarol* was found to cause a hemorrhagic syndrome in cattle eating moldy hay or sweet clover (Melilotus sp.) o Fungal spoilage of improperly cured hay caused coumarin, a natural compound in Melilotus sp., to convert to dicumarol which causes coagulopathy

a major concept in toxicity is the relationship of

dose and response: a toxic or adverse reaction to a chemical has a *threshold dose* above which detrimental effects can be measured. Most toxic responses increase in degree or severity (graded response) as dosage of intoxicant increases.

toxic dose-high (TDH)

dose that will produce drug-induced alterations and administration of twice this dose is lethal

acute copper poisoning in ruminants

drenches, footbaths-->diarrhea, liver damage, shock Acute Cu poisoning looks like As, Fe, Se toxicosis

factors affecting poison outcome: species

e.g. nitrate poisoning in ruminants vs monogastrics • Dogs and cats: similar dosage of nitrate; won't react as severely as small ruminants • Horses not as sensitive as ruminants to nitrate poisoning • Small ruminants metabolize nitrate to nitrite; has to have this metabolism to make toxic ○ Horses do that too but in cecum § If you expose horse and ruminant to same dosage, find that ruminants more sensitive because nitrate is going to be plentiful in the rumen § Horses, by time nitrate reaches cecum, mostly absorbed § Horses 1/3 as sensitive to nitrate as ruminants

clinical signs of zinc toxicity in dogs

early: vomiting, anorexia in several days: depression, diarrhea, weakness in advanced cases, hemolytic anemia leads to pale MM and icterus o Severe hemolytic anemia o High nucleated RBC; basophilic stippling o Polychromasia o Later, regenerative anemia o Increased serum alk phos, bilirubin o Hemoglobinuria, hematuria o Other changes of acute renal failure

absorption of mercury

elemental Hg poor GI absorption, but vapors are absorbed and dangerous salts and organomaterials are absorbed in GIT

metals exist as

elements or compounds - i.e pure metal...various salts...organic forms; solids, liquids, gases

Cholecalciferol (Vitamin D3)

essential nutrient with subtle, progressive and serious to fatal consequences

cathartics contraindicated in

existing diarrhea, absent bowel sounds, obstruction, corrosives

factors affecting poisoning outcome: pregnancy

exposure to abortion-inducing compounds

strychnine source

extract of South American tree, Stychnos-nux vomica indole alkaloid rodenticide: esp. gophers, ground squirrels 0.5% or less, baits usually dyed red or green baits only labeled for underground use

human medications that contain vitamin D

for psoriasis, osteoporosis, renal failure, hypoparathyroidism and other immune-mediated and inflammatory conditions that contain cholecalciferol analogs o Calcipitriene (Devonex®) Skin Cream o Increased number of formulations, indications and uses have increased the risk from this source o Often more concentrated and potent than rodenticides so much lower doses can result in toxicosis

methemoglobinemia

from oxidant effect of free copper

4 types of antagonisms

functional chemical dispositional receptor antagonists/blockers

used for plant treatment...fruits, vegetables, trees, crops, grasses - Agricultural - Home and garden • Food / produce protectants • *Wood preservatives*; most concerning generally safe last one is most toxic one

fungicides

(ROUNDUP) n-(phosphonomethyl) glycine (herbicide) Second most used herbicide in domestic, public, and agriculture environments. Wide margin of safety; intoxication has not been reported in pets. Toxicity related to surfactant (15%v/v): fluid and electrolyte loss. Ocular irritant, contact dermatitis

glyphosate; actually not that toxic

prognosis for anticoagulant poisoning

good to excellent

factors affecting poisoning outcome: sex

gossypol causes infertility in males

toxicity of OP's - Carbamates

high; doesn't take a lot to cause acute poisoning; some have LD50's less than 10 mg/kg not persistent in environment; degraded by sunlight and soil; short half life in environment; may persist in environment for 2-3 months as opposed to years in organochlorinated compounds

diagnosis of canine copper storage disease

history, liver biopsy -1. breed : bedlington terrier, westie, skye terrier (autosomal recessive abnormal biliary excrete) - Liver biopsy with copper concentration - Affected dogs have liver copper concentrations usually of greater than 1,000 ppm on a dry weight basis and frequently over 2,000 ppm - Dogs with secondary toxicity rarely have levels > 1,000 - Normal liver copper in dogs (dry weight basis) 90-350 ppm o values above 350 ppm are diagnostic 2o retention - Increase in ALT occurs late and reflects hepatocellular injury (as do elevated GT, hyperbilirubinemia, elevated PT and anemia) - Generally no increase in serum copper in affected dogs except during an acute hemolytic episode

Vitamin D toxicosis

in dogs and cats is usually secondary to ingestion of cholecalciferol (or its analogs) contained in rodenticides, human medications or, less commonly, dietary over-supplementation

gross lesions of paraquat

in lungs include congestion, hemorrhage, atelectasis, emphysema

clinical signs of metaldehyde

in minutes to several hours Anxiety Incoordination → m. tremors (jittery) → continuous spasms → seizures Hyperesthesia, opisthotonus Excitement may alternate with depression Hyperthermia (108oF), hyperpnea, acidosis Cats also show mydriasis, nystagmus Muscarinic signs from OPs or carbamates Very acute onset (minutes to hours) Hyperthermia ≥ 107-109 ̊ F/ 42 ̊-43 ̊ C o Muscle spasms may be the cause o One of the main factors contributing to the pathophysiology of metaldehyde toxicity as cell death in all organs occurs quickly at this body temperature Hyperpnea Hyperesthesia Depression alternating with hyperexcitability Salivation, diarrhea, vomiting Muscle tremors Opisthotonos Seizures (can have status epilepticus) Cats show mydriasis and nystagmus in addition

treatment for chronic copper poisoning in sheep

individual: -prognosis very guarded - Supportive care depends on kidney function - D-Penicillamine (52 mg/kg/day) o increase Cu excretion - TTM (tetrathiomolybdate) used in UK o not approved or commercially available in US -Avoid acsorbic acid?? Augments Cu liver toxicity flock: - Eliminate source of copper - Sodium molybdate (100 mg/hd/day) in feed for 3 weeks (10 lb of 2% premix/tn); not as drench, it's too much stress - Ground gypsum (calcium sulfate) 5 lb/ton of feed for 3 weeks - ZnO at 100 - 200 ppm reduces Cu absorption

other sources of Molybdenum

industrial, e.g. refractories (brick and tile manufacturing), aluminum and steel mills and fertilizers

tube for gastric lavage

largest tube possible

Which of the following statements is uncharacteristic of lead poisoning in cattle?

laryngeal paralysis and roaring is a common presentation (common in horses)

phenoxy herbicides used on

lawns, crops, pastures. Heavy use

rodenticides widely sold through

lay outlets (drug stores, etc.)

Human cases for over 2000 years - associated with use of metals - i.e. Romans lined copper wine vessels with lead to improve taste

lead

Perhaps the most common cause of heavy metal intoxication

lead

the king of toxic metals

lead • Long use in human history • Malleable and low melting point • Forms many compounds (oxides, halides, sulfides, proteinates) • No offensive taste or odor • *Highly cumulative in biological systems* Lead is a multisystem toxicant known to have caused poisoning in humans for > 2000 years The concentration of lead in the environment secondary to human redistribution has dramatically increased over hundreds of years and is a worldwide problem

Historical & continued cause of wildfowl losses

lead shot

Childhood lead poisoning

lead sources in the home → neurologic effects ...major public health issue, still today

anticoagulants accumulate and metabolized in

liver

lethal concentration (LC)

lowest concentration of compound in feed (or in water for fish) that causes death. it is expressed as mg of compound per kg of feed and water

lethal dose

lowest dose that causes death in any animal during the period of observation. Various percentages can be attached to the LD value to indicate doses required to kill 1% (LD1), 50% (LD50)1, or 100% (LD100) of the test animals. LD50 is commonly used measure of toxicity.

toxic dose-low (TDL)

lowest dose that will produce alterations; administration of twice this dose is not lethal

factors affecting poisoning outcome: chemical interactions

may alter absorption, protein binding, metabolism, excretion, etc. of one or both compounds: -additive (2+4=6) -synergistic (2+4=20) -potentiation (0+4=6) -antagonism (3+6=7; 5+0=2) • Simultaneous exposure to different compounds is the norm • Pyrethroids? • Some compounds may be competing for excretory pathways • Several ways interactions manifest themselves ○ Some additive ○ Some synergistic • Additive: two compounds which have effect through similar target, simultaneously ○ Both of them adding to the outcome (outcome is additive ○ Giving 2 different organophosphate compounds ○ Target: anti cholinesterase compound? • Synergistic: ○ One has less of effect ○ When present together: BOOM--exaggerated response ○ Example: § Alcohol and chloride? § Individually don't have much toxicity but when given together, synergistic § Why pharmacist says not to drink alcohol with medication • Potentiation: ○ One chemical not toxic but other is • Antagonism ○ Fundamental basis for development of antidotes ○ Barbiturates with vasopressor agent like norepinephrine May exaggerate or may subdue response

Snail and slug bait with highest hazard to dogs

metaldehyde

which system should you use?

metric

toxicity is usually expressed as

mg of toxicant per kg of body weight that will produce a defined biologic effect

Calculate Toxic Equivalent Concentration in Feed as % of B W

mg/kg feed = (mg toxicant/kg BW) x (BW of animal in Kg) (ppm) (BW of animal in Kg) x (% BW eaten as feed)* Simplified Formula - mg/kg feed x % BW eaten* = mg toxicant/kg BW - Or mg toxicant/kg BW (dosage) = % BW eaten* mg toxicant in feed/kg Previous example: 100 kg animal ate 2 kg of feed % BW eaten is 0.02 1000 mg/kg x .02 = 20 mg/kg (dosage) * % BW must be expressed as the ratio, i. e. 2% expressed as 0.02

factors affecting poisoning outcome: age

neonates and geriatric patients are generally more susceptible Don't have well developed toxin metabolism system so can't handle normal dosage Also BBB more patent allowing more passage of toxicants into brain Geriatric patients: generally more susceptible; enzymatic system apparatus has declined. Also fat content in body different from geriatric and neonate. Fat soluble compound: animals with more fat more susceptible

NOEL

no observed level effect

zinc hemolysis in birds?

no, only liver injuries

treatment for acute selenium poisoning

none effective - *General Rx for shock* *Antioxidants:* - Acetylcysteine (140 mg/ml) - Sodium thiosulfate (300-600 mg/kg IV) - large animals

lesions of chronic copper poisoning in sheep

o *icterus* (mucous membranes, body fat) o yellow friable liver o dark to black kidneys o dark red serum and urine

pharmacokinetics of vitamin D toxicity

o Absorption is rapid and complete in the small intestine o Circulates in plasma to liver and kidney o Metabolized to 25-hydroxy D3 in liver (cytochrome P450 dependant) o Kidney converts to toxic levels of 1,25 D3 Rate limiting step delays action Note that the onset of clinical signs may be as short as 8-12 hours with ingestion of toxic amounts of cholecalciferol analogs such as those in human medications as they can speed up this rate limiting step o D3 metabolites excreted mainly via bile to the feces o Canine daily requirement is 22 IU (0.55μg/kg/day) according to the National Research Council

ddx for zinc toxicity in dogs

o Autoimmune hemolytic anemia o Onion & garlic poisoning o Mothballs (napthlene) o Lead+

sources of copper for all animals

o Cattle feeding poultry litter, veal calf rations > 100 ppm o Swine contaminated feed > 250 ppm o Sheep - most sensitive to elevated feed levels >15 ppm Cu predisposes to copper accumulation o Plants reflect soil levels Midwest grains/forages are 6 - 11 ppm Cu and <1 ppm Mo o Cattle, swine, poultry feeds and supplements often high (~250 ppm) in copper o General livestock mineral mixes = high in copper o Contamination of sheep feeds during mixing or delivery o Drenches o Footbaths

toxicity of vitamin D

o Cholecalciferol Dogs can die from dose as low as 5 mg/kg 1 - 3 mg/kg = toxic (= 2.6 g bait/kg)?? 10 - 20 mg/kg single oral is lethal o Calcipitriol (dihydroxy D3 analog) toxic 50 μg/kg o Gen'l Susceptibility: Cats > Pups > Adult dogs

mechanism of action of vitamin D toxicity

o Cholecalciferolrenal 1, 25-dihydroxyvitamin D o Increase in serum Ca++ levels by ... increasing Ca++ (and PO4) absorption from gut via PTH and increase osteoclast bone resorption renal retention of Ca via distal tubule resorption o Persistent hypercalcemia & hyperphosphatemia o Early renal tubular damage & necrosis o Abnormal soft tissue mineralization - renal tubules and small arterioles

pathological findings of vitamin D toxicity

o Early: Renal tubular necrosis o Mineralization in kidney, heart, lung, stomach, intestine o Aortic plaques o Thyroid hypertrophy/hyperplasia o Renal cortex red-gray o Kidney tissue calcium and phosphorus level - with toxicosis... Ca elevated to 2000 - 3000 ppm (normal < 600) Ca/P ratio elevated @ 0.4 - 0.79 (normal < 0.2)

toxicokinetics (ADME) of zinc

o Excreted primarily via the bile and pancreas o Interferes with absorption and utilization of iron and copper o Absorption inhibited by Ca, Cd, Cu, protein and phytic acid o Mucosal irritation from ingestion of some zinc salts (e.g., zinc oxide) o Approximately 2/3 of zinc is loosely bound to protein in serum or plasma. Remainder is tightly bound

supportive therapeutics for rodenticide toxicity

o Handle with care! o Stabilize and treat shock o Relieve hemothorax Inpatient care until coagulopathy is stabilized

lesions of canine copper storage disease

o Hepatomegaly or small liver (microhepatica) o Prominent cytoplasmic granules in hepatocytes o Focal hepatitis; focal cirrhosis o Chronic *active hepatitis* o *Generalized cirrhosis*

effect of vitamin D toxicity on heart

o Hypercalcemiaconduction dysfunction o shortened Q-T segment and increased P-R o bradycardia with increased heart sounds o vasoconstriction and hypertension o heart failure may ensue

clinical signs of acute copper toxicity

o Lethargy o Anorexia o Diarrhea o Liver damage o Shock from Cu salts o Hemolytic crisis and hemoglobinuria 3 days after exposure if animal survives the GI signs * Acute Cu poisoning looks like As, Fe, Se toxicosis

The major metabolic roles of the RBC

o Maintain membrane and its deformability o Maintain critical ion concentrations via Na+K+/ ATPase Pump o Maintain reducing potential via NADH-NADPH to protect hgb and enzymes from oxidative risk o Energy source is glucose, and insulin is not required for entry into cells. o Metabolism is via anaerobic glycolysis and the pentose phosphate pathway (PPP) susceptible to oxidative stress prevent oxidation of hemoglobin

lead clinical signs common to most species

o Onset: several days after exposure o Signs: quitevariable low vs explosive Gastrointestinal + neurological combo Complete anorexia CNS can be depressive or convulsive o Species differences are important

Zinc soures

o Pennies minted after 1983 (98% Zn: 2% Cu) o Zinc cages and hardware/galvanized wire or hardware o Ointments o Supplements o Zinc game pieces from board games o Zinc oxide ointments (ZnO = 80.4% Zn) o Zinc feed supplements (large animals) o Electrical pastes, fumes, paints, dust o Anti-dandruff shampoo (zinc pyrithione)

pharmacokinetics of bromethalin

o Rapidly absorbed in the gastrointestinal tract with peak plasma concentrations occuring in about 4 hours o Parent compound metabolized in the liver by mixed function oxidases to the more toxic metabolite, N-desmethyl bromethaline note~guinea pigs cannot metabolize bromethalin to desmethyl bromethalin and consequently have a MUCH higher threshold for toxicosis o Excretion is mostly through bile with a small amount excreted in the urine This is one reason disruption of enterohepatic circulation is key to treatment

other lab abnormalities of vitamin D toxicity

o Serum Ca++ > 12 mg/dL do initially and repeat in 12 hours o Hyposthenuria (urine specific gravity ~ 1.002 - 1.006) o Increased BUN and creatinine o Increased vitamin D metabolites: 1,25-dihydroxy D3 (not increased in other differential diagnoses)

general clinical features of vitamin D toxicity

o Usually start between 12-36 hours after ingestion depending on the compound and individual animal response (which can be highly variable) o Anorexia, depression, muscle weakness, dehydration

mechanism of action of zinc toxicity

o Valence +2 interacts with other divalent cations, e.g. calcium, copper, lead o Required for metalloenzymes in animals

potency of vitamin D forms

o Vitamin D2 (ergocalciferol) is the synthetic form of vitamin D o Vitamin D2 crystals have a potency of 40 units of vitamin D (USP) per microgram o One mg of cholecalciferol is equivalent to 40,000 international units of vitamin D. o One USP or international unit is equal to 25 ng of cholecalciferol or ergocalciferol.

GI effects of vitamin D toxicity

o Vomiting o Gastric ulceration omelena/hematochezia/hematemesis with advanced cases

risk factors for vitamin D toxicity

o breeds with tendencies toward hypercalcemic disorders (e.g. Keeshonds with primary hyperparathyroidism) o suckling offspring @ risk as vitamin D is fat soluable and transmitted via milk during lactation

One USP or international unit is equal to 25 ng

of cholecalciferol or ergocalciferol.

Environments with higher risk of lead poisoning for small animals include

older or lower income areas, as well as buildings being renovated; large animals in older buildings and "casually maintained" environments at higher risk

generally use cathartics only

once

selective herbicides

only harms certain plants e.g. 2,4-D (chlorophenoxy group) ...broadleaf weeds--24d is broadleaf herbicide

4-Aminopyridine (Avitrol®) toxicity signs

onset 15 min - hyperexcitable, tremors, salivation, incoordination - convulsions, cardiac and respiratory arrest ( early clinical signs very similar to strychnine)

clinical signs of strychnine

onset 15 min to 2 hrs rarely vomit early nervous, restless, muscle tremors "saw horse" stance extremely sensitive to external stimuli (touch, sound, light) explosive onset of tonic to tetanic seizures, whole body rigid death from anoxia Onset: 10 to 120 minutes after ingestion. Even sublethal doses may cause elevated blood pressure and heart rate. Usually no vomiting. Anxiety, stiffness. Violent tetanic seizures. Spontaneous or initiated by numerous stimuli, which is a diagnostic feature, however it can be hazardous (and lethal) to deliberately initiate such seizures. Initiation of seizures is therefore contraindicated. Saw-horse stance. Opisthotonus and persistent rigid extension of all four limbs. Generally, there are no paddling and no running movements, masticatory activity, or salivation. Facial musculature contraction causes strained expression. Rigidity inhibits respiration, apnea results. Periods of relaxation gradually become fewer and shorter. Rarely loss of consciousness. Death from anoxia and exhaustion. Myoglobinuria possible.

zinc phosphide clinical signs

onset in 15 min → 7 hrs • *Vomiting* (bloody) • Anorexia • Lethargy • Rapid deep respirations • Abdominal pain • Ataxia, weakness • Also *seizures*, running and/or hyperesthesia • SIGNS QUITE VARIABLE - Difficult DDx

clinical signs of OP's - carbamates

onset usually acute, minutes to hours Parasympathetic stimulation...muscarinic emesis, salivation, lacrimation, urination, defecation, bronchoconstriction, miosis, bradycardia ; due stimulation of PNS. Neuromuscular... i.e. "nicotinic effects" muscle tremors, stiffness, paralysis • CNS... apprehension, nervousness, seizures ● Death from respiratory failure due to bronchoconstriction; usually die due to respiratory failure. contributed to by paralysis which is due to effect on the nicotinocides at neuromuscular junctions.

Guidelines for direct removal of the toxicant and/or metabolites from circulation

overall clearance should be significant so as to sufficiently alter t1/2 of elimination of the compound in question. Ideal for low MW (<500 daltons), water soluble compounds, with low protein binding, i.e. small volume of distribution Recommended in cases of renal failure or If a lethal dose is involved

Chemical concentrations in clinical toxicology are often expressed in

parts per million (ppm), parts per billion (ppb) or parts per trillion (ppt)

therapy for canine copper storage disease

penicillamine, Zn Penicillamine (Cuprimine®) o chronic administration (10-15 mg/kg p.o. q12h) Zinc Glucocorticoids o for lysosomal stabilization in acute disease Ascorbic acid o 500 - 1,000 mg/day, to enhance urinary excretion of copper 2,3,2-tetramine o 15 mg/kg p.o. q12h o has been used as a chelator for copper in Bedlington terriers; o not commercially available Vitamin E o 200-600 IU q24h for oxidative liver damage

toxin

poisons that originate from biologic processes; generally classified as biotoxins but also zoo toxins (animals, snakes, insects, etc.), mycotoxins (fungal), plants (phytotoxins), algae (phycotoxins)

most important factor in handling a poisoned animal

quick accurate diagnosis

mechanism of strychnine

rapidly absorbed antagonizes glycine, the neurotransmitter in the inhibitory internuncial neurons (Renshaw cells) of the spinal cord and medulla inhibitory effects of the reflex arcs are lost, leading to uncontrolled excitation of the spinal reflex, extensors muscles predominate excreted through the urine Strychnine acts by competitively and reversibly antagonizing the inhibitory neurotransmitter glycine at postsynaptic neuronal sites in the spinal cord and medulla. Result is unchecked reflex stimulation, with predominance of more powerful extensors which results in rigidity

Manipulation of numbers and estimation of dosage

re basic to the practice of medicine (Table 1-4). 1. Calculating concentrations and estimating dosages are essential to the interpretation of toxicology data resulting from laboratory analyses or estimates of probable exposure. The toxicologist calculates drug dosages based on estimates of body weight and food consumption (Table 1-5). The practitioner must determine if clinical poisoning is probable by relating a level of contamination in feed or forage to a known toxic dosage. 2. Failure to consider dose versus response is a common problem in clinical toxicology. 3. Toxicology calculations require familiarity with the metric system. Useful metric units and abbreviations used in toxicology calculations are listed in Table 1-6.

anticoagulant

rodenticides that interfere with Vitamin K dependent clotting factors

• Natural insecticide, alkaloid; very unstable in environment and decomposes quickly when exposed to light and air and oxygen

rotenoid

• Flea control, premise insecticides, cattle grubs • Ticks, lice etc in dogs

rotenone

• Toxic to fish - sometimes used for control of "rough" or unwanted fish. • Toxic to fish at < 75ug/L water -used as pesticide to get rid of unwanted fish

rotenone

Ideal candidates for direct removal of the toxicant and/or metabolites from circulation

salicylates, barbiturates, ethylene glycol, lithium, bromide, theophylline

can combine AC with

saline or sorbitol cathartic

what generation anticoagulant is d-con?

second

chronic copper poisoning in sheep

sheep sensitive to elevated feed levels... >15 ppm Cu predisposes to copper accumulation molybdenum also plays a role. addition of 2 ppm Mo (as sodium molybdate) to sheep feeds approved since 1987) role of molybdenum in ration: optimum 6 Cu : 1 Mo tolerated 10 Cu: 1 Mo *sulfur*, zinc, iron also affect cu uptake from diet

clinical signs of amitraz toxicity

signs are dose related; onset in 2 - 4 hrs ● At *therapeutic doses*, transient sedation of 2 to 6 hour duration and mild gastrointestinal signs of anorexia, vomiting, diarrhea may be seen ● Poisoning more likely in the old, debilitated & diabetic ● With *higher doses*: *CNS depression*, ataxia, mydriasis, hypothermia, *hyperglycemia*, bradycardia, hypotension, muscular weakness, emesis, uncontrolled vocal spasm and micturition have been noted - in horses, colic from g.i. stasis - may be fatal

use _________ ___________to trap weakly acidic drugs e.g.. salicylates, ethylene glycol, barbiturates in alkaline urine

sodium bicarbonate

factors affecting poisoning outcome: lactation

some ergot alkaloids inhibit lactation

Feed intake varies with

species, size, age and production or work of animals.

Cotton insecticide use by family (million lbs)

sprays, dips, pour ons can be used as insecticides on animals but also on crops

greater incidence of lead poisoning in

spring and summer

when to start therapy for anticoagulants

start Therapy if Dosage estimate is 1⁄4 of LD10! (LD10 not published; dosage that would kill 10% of population) Can also go by guideline: if LD50 15, start treating animal at 1.5 mg/kg body weight. Could have clinical signs like anemia, bleeding, death so treatment recommended as a guide (divide LD50 by 10)

Mo toxicosis (Cu deficiency) is enhanced by dietary

sulfate

toxicity

the amount of poison that, under specific conditions, causes toxic effects or detrimental biologic changes -ability to produce poisoning often expressed as mg toxicant per kg body weight..*mg/kg* -the acute "*toxicity*" of arsenic is 5mg/kg body weight f

hazard or risk

the probability that a chemical will cause harm under specific conditions of use. -compounds of high inherent toxicity may pose little risk if access or exposure of animals is limited. -materials of low toxicity may be dangerous if used extensively or carelessly -the ratio between inherent toxicity and use or exposure level can be used to compare relative risk • In clinical toxicology, risk and hazard the same thing • Monensin has higher toxicity compared to urea ○ Takes less monensin but its use level is small so you have better safety margin when giving monensin § Less likely to have risk for monensin if properly have good inclusion rate in feed • Use rate of urea high: higher risk of toxicity Likelihood of poisoning under conditions of usage higher for urea

sub chronic toxicity

the study of exposure and effects for 1-3 months. Studies of 3 months are considered adequate to express all forms of toxicosis except carcinogenic effects and multigenerational (reproductive) effects

toxicology

the study of poisons -includes the identification of poisons, their chemical properties, and their biologic effects as well as the treatment of disease conditions they cause

dose

the total amount of toxicant received per animal

In order to understand the basis of heavy metal toxicity, be familiar with

their chemical properties and reactivity. • A. Oxidation states • B. Bonding

can become poisons under certain conditions

therapeutic drugs and essential nutrients

One mg of cholecalciferol is equivalent

to 40,000 international units of vitamin D.

The idea behind ion trapping is

to acidify or alkalinize plasma to optimize urinary excretion of the toxicant. Trap the toxicant or its metabolites in urine Drugs and some other toxic compounds are weak acids or weak bases and in solution become ionized by gaining or losing hydrogen ions. • At physiologic pH most drugs are partially ionized. The extent of ionization depends on the dissociation constant (Ka) and the pH of the medium. • The pKa of the drug/toxicant is the pH at which equal amounts of the chemical/drug is in the ionized (polar) form and the unionized (nonpolar) form. • Weak acids have pKa between 3.0 and 7.5. Weak bases have pKa between 7.5 and 10.5. Cells are more permeable to nonpolar drug/toxicant forms, which easily diffuse across cell and tubular membranes and are reabsorbed. The goal of forced diuresis with pH alteration is to enhance urinary excretion of the toxicant by increasing the amount of ionized forms in urine, and to trap them in urine. Strong acids (pKa < 4) and strong alkali (pKa > 8) are already ionized and need no manipulation. •The reverse is true for absorption in the stomach. In acidic solutions/environment, weak acids such as salicylates are less ionized and more easily absorbed. Weak bases are trapped in the stomach (acid environment) and more easily absorbed in the more alkaline medium e.g.. duodenum. Generally, weak acids are better candidates for enhanced excretion because they tend to remain in plasma (have smaller volumes of distribution) which has a higher pH (7.4) than intracellular fluids (pH = 7.0). Weak bases are less ideal for excretion because they more easily enter cells where they are trapped in the more acidic intracellular environment and as such are less available to the kidney for excretion.

use ____________ _______________

to acidify urine to trap weakly basic drugs such as amphetamines

Prolonged exposure to a toxicant may allow animals to develop

tolerance to the toxicant so that the size of the dose required to produce lethality upon repeated exposure increases. This is often due to an increase in the metabolic detoxification of the compound.

P=O is more

toxic

another term for poison

toxicant (less harsh; especially feed additives, drugs, etc.)

toxicity and dosage in wildlife or fish

toxicity may be expressed as the concentration of the substance in the feed or water, where dosage is directly correlated with concentration when the material is freely available

Oxidative desulfuration (P=SP=O) increases

toxicity; This is done by Phase I Mixed Function Oxidases (lethal synthesis)

True or False? In excessive vitamin D exposure, both 25 hydroxy Vitamin D3 and 1,25 hydroxy vitamin D3 are active toxic metabolites

true

Water intake is roughly

twice the feed intake, by weight, but also varies with environmental conditions.

anticoagulants excreted via

urine and bile; some transfer to milk placental transfer suspected

in stomach (acidic solutions/environments) _____ _______ such as salicylates are less ionized and more easily absorbed.,

weak acids Weak bases are trapped in the stomach (acid environment) and more easily absorbed in the more alkaline medium e.g.. duodenum.

less ideal for excretion because they more easily enter cells where they are trapped in the more acidic intracellular environment and as such are less available to the kidney for excretion.

weak bases

What is the ideal sample of choice for diagnosis of anticoagulant rodenticide intoxication in live animals?

whole blood

imidacloprid (1994)

• *Advantage®* (Bayer) flea control • *Premise®* for termites, Merit® for lawn grubs, *Gaucho* for crop seeds - *blocks post synaptic nicotinic acetylcholine receptors in insects* - no adverse reactions reported up to 5X dosage in dog - possible hair loss at point of application especially at high (10X) doses - Dogs tolerated 500 ppm in diet for 1 year - 95% excreted in 48 hours - anecdotal toxicoses unsubstantiated takes advantage of unique metabolism of insects, fleas, mites, pests targets metabolism or growth regulation overall going to be safe when animals get into them; less potent; need to ingest a lot to be intoxicated may be found in combinations: one that targets growth metamorphosis or combined with products; growth regulators with insecticides neonicotindes work in same mechanism

Environmental and Food safety impact of Chlorinated pesticides

• *All animal species are targets* • Potential for relay intoxications exist • Eggshell thinning in birds; major reason for banning these compounds; estrogenic and proper mineralization of egg shells--were breaking causing population declines; bald eagles have higher concentrations because eating smaller animal species • Biomagnification • Food safety impact Residue awareness and restrictions - Reportable disease: report to public health or FDA

treatment for phenoxy herbicides

• *Detoxification*: Emesis & AC early - Dermal: Wash with soap; flush with water - Diuresis possible help for excretion • Rx NO specific antidote available • Recovering animals: Bland high quality diet

lead pathology in cattle

• *Few significant gross lesions*... • *Lead objects in rumen or stomach* • Rumen protozoa dead or inactive • *Laminar cortical necrosis* (DDx from PEM) • Inconsistent acidophilic intra-nuclear inclusions in renal tubules • Porphyrinuria

lead toxicity clinical signs in dogs

• *GI* - vomiting , *anorexia*, tender abdomen, diarrhea/constipation • CNS - *lethargy*, hysteria, *convulsions*, ataxia, blindness, mydriasis • Clinical-pathincreased nucleated RBCs and basophilic stippling without severe anemia • Overall features - *Mainly GI* and neurologic - *GI signs usually appear first* - CNS more likely in young animals

lead toxicity in cats : clinical signs

• *Lethargy, anorexia*, vomiting, *weight loss*, excessive salivation • *Neurologic signs* can be minimal • Inconsistent nucleated RBCs and basophilic stippling • Elevated AST, ALP • DDx: OPs. Bromethalin, methylxanthines Hepatic encephalopathy Clinical signs o Lethargy, anorexia, vomiting, weight loss, excessive salivation o Neurologic signs can be minimal Pathologic findings o Inconsistent nucleated RBCs and basophilic stippling Laboratory findings o Elevated AST, ALP Differential diagnoses o OPs o Bromethalin o Methylxanthines o Hepatic encephalopathy

Cholecalciferol *Sources* (Vitamin D3)

• *Rampage®, Quintox®, Ortho Mouse-B-Gone®* • pellet or cereal based baits contain 0.075% active ingredient • used in "place packs" @ 10 - 30 grams each • careless placement of baits = toxicosis • *toxicosisinrodentsdelayed2-3daysaftersingle ingestion* • 1 IU of D3 = 0.025 ug Cholecalciferol - *Or 1 ug D3 = 40 IU D3 (1 mg D3= 40,000 IU)*

lead toxicity therapy

• *Remove animal from source • Stop further absorption* - Decontaminate GI tract...cathartics, enemas according to species - Endoscopy or gastrotomy to remove objects - Oral MgSO4 in cattle - laxative and formation of insoluble PbSO4 - *Charcoal not effective for metals* Remove animal from source Stop further absorption o Decontaminate GI tract cathartics, enemas according to species, endoscope or gastrotomy to remove objects oral MgSO4 in cattle laxative and formation of insoluble PbS • *Supportive* - Fluids, *thiamine* - *Control seizures*: valium, pentobarbital + Mannitol, dexamethasone for cerebral edema - Antioxidants (vit C, E); N-acetylcysteine - Good nursing care

Dx:Lesions & Clinical Chemistry of phenoxy herbicides

• *↑ALP and CPK* consistent with mild liver, kidney and muscle damage • Oral ulcers, swollen liver and/or kidneys in all animals • Mild to moderate renal tubular injury • *Chemical analysis of forages & rumen, urine*

Percentage Equivalent of 1 ppm

• 1 ppm = 1 mg/kg = 1 mg/1,000,000 mg • 1/1,000,000 = 0.000001 • Convert to % by multiplying by 100 0.000001 x 100 = 0.0001% • Thus, 1 ppm is 0.0001% • NOTE: Moving decimal point 4 places right from the stated percentage = ppm e.g. 1% 10,000 ppm • Move 4 places left to convert from ppm to % e.g. 0.0001%1 ppm

paraquat toxicity

• 25 - 75 mg/kg orally in domestic animals • Turkeys more resistant (290 mg/kg) • Dogs @ 170 ppm in diet for 60 day - toxic - Anorexia,

Starlicide

• 3-Chloro-4-methylaniline (3-chloro-p- toluidine) • Starlings, gulls, other avians are target species • Mammals less sensitive • It is a nephrotoxicant • Proximate nephrotoxic mechanisms are not defined • LD50 in starlings is 3.8 mg/kg bw • High chronicity factor (4.7 ppm over 30 days Vs 1 ppm for 90 days)

chronic selenium poisoning

• 5 - 40 ppm Se in plants • Traditionally a problem in the northern great plains • Secondary accumulator plants bring Se to surface, make it available to crop plants (e.g. wheat) Clinical signs: lameness, hoof malformations, hair loss from tail/mane

post mortem diagnosis

• A complete necropsy is recommended. - may gain obvious clues for the cause of death. e.g.. Japanese yew, or copper poisoning in sheep, anticoagulant rodenticide. - Also important should litigation become an issue. - Insured patients: Pay particular attention.Take photographs! • Gross findings of each organ. - Check the GIT contents thoroughly • Collect samples for both analytical toxicology and for histopathology • Microscopic findings are important: *Absence of lesions is as important as presence of lesions*

What is a pesticide?

• A poison used to destroy pests of any kind.

toxicokinetics of cholecalciferol

• Absorption - rapid and complete in S.I. • Circulates in plasma to liver and kidney - Metabolized to 25-hydroxy D3 in liver - Cyt P450 dependent • Kidney converts to toxic 1,25 dihydroxy -Rate limiting stepdelays action • D3 metabolites excreted mainly via bile to the feces. • K9 daily requirement is 22 IU (0.55μg/kg/day) -month of treatment after exposure until calcium reduced

orgonosphates ADME

• Absorption rapid by oral, dermal, inhalation • Distributed in plasma-->liere-->rCNS; metabolized in liver. CNS the primary target organ. • Metabolized by MFO system (oxidation) - Deactivated by Hydrolysis • Excretion of metabolites in urine and feces -kideny excretion -depending if chlorinated-->feces; some of the more toxic compounds have been used in chemical warfare agents agent exposures present with similar clinical syndromes but not common

treatment of nicotine

• Activated charcoal, • *Artificial respiration*, oxygen as needed • IV fluids to promote excretion • Musclerelaxants • *Acidification of urine promotes ion trapping in urine* • No antacids!! - promote Nicotine absorption • Atropine??? -impaction after eating cigarette buds -if topical, wash animal so whatever that was on skin is removed

amitraz mechanism

• Acts as an *alpha 2 adrenergic agonist* (similar to xylazine), g.i. stasis, bradycardia, depression, *increased blood glucose*, sedation • Rapid oral absorption, plasma peak = 5 hr • Half life is 24 hrs -hard to metabolize--good thing half life is short main clinical presentation is sedation and depression and bradycardia

3 clinical syndromes of selenium

• Acute: high dosage exposures (*looks like acute arsenic, iron, copper, chromium* and other metals).. *GI changes* • Subacute: 1-4 weeks duration; *neurologic and dermal changes* • Chronic: Weeks to months; dietary contamination or plant sources. ↓Performance, *alopecia, lameness*

Environmental and Food safety impact of OP and Carbamates

• All animal species are targets - Cats, fish and birds most sensitive • Secondary intoxications reported; predators eating animals that have died of OP • Food safety impact Do NOT eat!!!; will be in meat tissues BIRDS AND FISH MOST SENSITIVE -gulf courses sprayed; animal pick up insects-->victims

environmental and food safety impact of strychnine

• All animal species are targets • High probability of relay toxicosis exists • Food safety impact is not known

Environmental and Food safety impact of metaldehyde

• All animal species are targets • Low probability for relay intoxications • Food safety impact is not known

Environmental and Food safety impact for Bromethalin

• All animal species are targets • Low probability for relay intoxications • Food safety impact is not known - Fat soluble....so can pass in milk

Environmental and Food safety impact of cholecalciferol

• All animal species are targets • Potential for secondary intoxications exist • Excreted in milk

Environmental and Food safety impact of Avitrol

• All animal species are targets • Mass deaths reported in birds • Potential for relay intoxications exist • Food safety impact is not known

diagnosis of inorganic arsenic

• Arsenic analysis of kidney, liver > 8 ppm ( but excreted quickly) • Suspect material • [Blood is not a good diagnostic source] • Urine contains arsenic if kidneys are functioning • Accumulates in hair for chronic exposure

The toxic level of feed additive X in feed for a 10 lb pig is 25 ppm. What is the toxic dosage of X on a mg/kg basis?

• Assume pigs eat 8% of their body weight of feed/day • Use [Level in feed (ppm) X Kg feed eaten]/body wt (kg) • [25 ppm x 0.36 kg feed]/4.535 kg = 1.98 mg/kg

Relationship of Feed Intake to Toxic Feed Concentration

• At a toxic dosage of 1 mg/kg BW.... ....And Feed intake shown, the toxic level is

OP's - carbamates treatment

• Atropine sulfate (1/4 iv, rest SQ) (bid - tid); antidote - small animals...0.2 mg/kg - large animals...0.5mg/kg Atropine loses efficacy after 2-3 doses Do not over atropinize - atropine competes with excess acetylcholine; if have cholinergic crisis, competes for sites therefore can give relief. -short half life compared to OP compounds; give every 6 hours or so and make sure animal not over atropinized -horses especially sensitive to over atroponizing and may develop ileum -generally good indication you have reached efficacy if you can grab tongue of large animal; atropine will have stopped excess salivation so you can grab tongue -multiple exposures-- with every exposure efficacy decreased; don't know reason for that alternative: • Atropine sulfate (1/4 iv, rest SQ) -Glycopyrrolate - alternative to atropine, doesn't cross blood-brain barrier like atropine does • Oral activated charcoal; 2-pam • Atropine sulfate (1/4 iv, rest SQ) - Glycopyrrolate • Oral activated charcoal • "Reactivator" oximes like 2-PAM to pull pesticide from enzyme (Sm. An.) ; generally effective within 12 hours. - Must give before aging (AChE Irreversible binding) - Not for carbamates - they spontaneously hydrolyze; bond with enzymes no strong so have regeneration • Dermal: wash with soap and water

lead mechanism of action

• Binding to sulfhydryl groups - *Heme synthesis* - Altered GABA transmission • *Competition with divalent cations eg Ca++ ions* - Displace Ca++ from binding proteins - Altered nerve and muscle transmission • Inhibition of membrane assoc. enzymes - Calmodulin, Na/K pumps • *Altered vitamin D metabolism* - Impaired Ca++ absorption & Zn related enzymes *Competition with Ca* in many systems interferes with multiple functions

toxicity doses of chlorinated hydrocarbons

• Cats most sensitive - LD50 3-6 mg/kg • Dog LD50 is 50-65 mg/kg • Cattle Minimum Toxic Dose: 10-25 mg/kg; need to watch for passing in milk due to residues • May be cumulative in all species - based on lipophilic nature of products • Lindane for ectoparasites in dogs is potential iatrogenic or accidental exposure. - Toxicity: LD50 - cat 25 mg/kg; dog 40 mg/kg -need to report to state vet

permethrin in cats

• Cats: Highest risk for pyrethroid intoxications • Toxicosis has occurred from contact with - spot-on treated dogs • Onset 2 minutes - 3 hours • Hyper salivation, vomiting, seizures, paw shaking, ear twitching, flicking of tail, twitching of dorsal skin • Agitation, seizures can occur 12 - 24 hours post exposure • Seizures may be difficult to control -no specific antidote

phenoxy toxicity dosages

• Cattle: 200 mg/kg acute toxic dosage, or 100 mg/kg for 10-30 days; nitrate? • *Dogs: 100 mg/kg LD50 in dogs*; more sensitive than other species • Dog: Multiple lethal dosage 25 mg/kg 6 days • Dogs tolerate 500 ppm in diet for 2 years • Cattle tolerate 2000 ppm long term cumulative; higher chronicity factor; a few dosages will cause clinical intoxication as opposed to single dosage of 100 mg/kg body weight

differentials for amitraz

• Causes of CNS depression.... - Ivermectin - Barbiturates - Cannabinoids

about arsenic

• Chemistry - metalloid 1. Elemental, organic, inorganic 2. Trivalent (+3) comes as organic and inorganic 3. Pentavalent (+5) comes as organic and inorganic

Insecticides: Classical

• Chlorinated Hydrocarbons • Pyrethrins and Pyrethroids • Organophosphates • Carbamates • Formamidine (amitraz) - Mitaban®, Taktic® classical ones not very selective;

summary of insecticides

• Chlorinated Hydrocarbons - rare (CNS +) • Organophosphates and Carbamates - ( AChE = ACh excess) • Formamidine (amitraz) - Mitaban®, Taktic® > (CNS depression) • Pyrethrins and Pyrethroids (CNS/PNS excitation, transient, cats mostly affected) • Others - Nicotine (Ach receptor agonist) Rotenone = (mitochondrial toxin, interferes with ATP synthesis)

lead clinical signs

• Clinical onset usually delayed several days - Time for absorption, binding to active sites • Depends on form of lead Organic - rapidly absorbed and distributed Metallic - slower absorption & onset Carbonate, nitrate, oxide salts > acetate & chloride salts • *Onset = several days after exposure* • Signs quite variable: slow vs explosive • *Gastrointestinal + Neurological combo* • Complete anorexia • CNS depression or convulsion • *Species differences are important* The primary manifestations are gastrointestinal and neurological and young animals are particularly susceptible

diagnosis of chlorinated hydrocarbons

• Clinical pathology/chemistry not helpful • Acute: measure residues in Stomach/rumen contents, *brain*, liver, feed, suspect material - Residues: Body fat (tail head), milk, eggs - Long half-life w/ 2 compartment kinetics; periodic fat biopsies from tail head need to be taken to make sure concentration in fat is low • Histopathology unremarkable

rodenticide risk

• Common cause of poisoning in pets • Many kinds: include anticoagulants, Bromethalin, Cholecalciferol, strychnine and zinc phosphide • Wide range of clinical response • Some potential for secondary poisoning

about iron

• Common in human dietary supplements and vitamin/ mineral tablets • Ingestion of concentrated iron sources can be toxic to children and pets ● Injections

food safety impact of anticoagulnats

• Danger of getting into the food chain - Used in and around farm animal houses

ddx for anticoagulant poisoning

• Dicoumarol - livestock via moldy hay • Idiopathic coagulopathy • Autoimmune thrombocytopenia • DIC • Hereditary (Von Willebrand's Disease) • Liver disease ( clotting factor synthesis)

Novel Insecticides/Repellents

• Diethyltoluamide (DEET) • Fipronil (phenylpyrazole) - Combat®, Frontline®, Maxforce®fleas, ticks • Imidacloprid (neonicotinoid) - Advantage®, Gaucho®, Premis®crops, termites, fleas • Hydramethylnon (trifluoro methy amino- hydrazone) - Amdro®, Maxforce®, Impact®

Zinc phosphide Diagnosis

• Difficult - signs are non-specific & variable • History of exposure • *"dead fish" or garlic odor* may suggest • Hepatic fatty change, mycoardial & renal tubular damage, lung edema • Volatile - collect tissue, freeze & seal • *Zinc phosphide in stomach contents* by gas chromatography/mass spectrometry

mechanisms of actions of chlorinated hydrocarbons

• Diphenyl aliphatics eg DDT: Interfere with Na+ flow in nerve membranes → slows Na+ influx and inhibits K+ outflow. - Lowers threshold for another action potential thus, enhanced initiation of action potentials • Cyclodienes (and possibly aryl hydrocarbons) inhibit postsynaptic binding of GABA allowing stimulation of the neuron.

Paraquat (1,1'-dimethyl-4,4'-bipyridyl)

• Dipyridyl class herbicide • Classified as Plant dessicant • Non-selective, degrades in sunlight in 3 wk • Binds to clays; inactivated in soil • Uses: quick kill; defoliation before harvest • Application rate 0.5 lb/a Diquat Paraquat's cousin; Paraquat targets lungs while diquat is renal toxicant--nephrotoxicity and ARF

pyrethrin/pyrethroid treatments

• Discontinue exposure, control the tremors, and support the animal - bathe with detergent - for tremors... methocarbamol (Robaxin) - most animals recover in 24 - 72 hrs • Alternatively, valium, or pentobarbital - supportive care; fluids, and thermoregulation to control hyperthermia - Check for hypoglycemia (old or young cats) and treat as needed

toxic dosages of cholecalciferol

• Dogs can die from dose as low as 5 mg/kg • 1 - 3 mg/kg = toxic (= 2.6 g bait/kg BW) • Calcipotriol (Dovonex) toxic 50 μg/kg • Gen'l Susceptibility: Cats > Pups > Adult dogs

lead toxicokinetics

• Dust inhalation...fine particles < 0.5 μm • Lead shot/bullets in tissue...what happens? • 90% binds to RBC, some to albumin • Concentrated in gut--->Liv, lung, kid Bone storage • Young animals BBBbrain • Crosses placenta to fetus abortion, brain damage • Secreted in milk • Excreted primarily in feces, less in urine 1. Ingested lead typically requires solubilizing *Acidic environment of stomach* vs. lead in soft tissue 2. Tissue binding - first to *erythrocytes* 3. Crosses blood-brain barrier and placenta - Embryo toxicity 4. Incorporation into *bone*: storage site, detoxification mechanism - *Lead line: in radiographs*, in gums 5. Elimination -*Fecal*, urinary Absorption in the small intestine is poor (in a mature animal only approximately 2% of ingested lead is retained) Young animals have a much higher need for Ca++ so the absorption of lead is significantly higher (remember lead competes with calcium and the transport system in the intestinal tract may actually favor lead over calcium) Absorption is maximized when lead is in small, divided particles such as dust particles < 0.5μm in size o Blood is the primary site for distribution with > 90% bound to RBC's. Lead is stored in soft tissues for up to 4-6 weeks and chronically stored in bone (can be decades) o Excretion is primarily via feces o Toxicity is dependent on the form of lead, age of animal and amount/duration of exposure Carbonate, nitrate, oxide salts > acetate & chloride salts Formoflead 1 Organic - rapidly absorbed and distributed Metallic - slower absorption & onset Onset usually delayed several days Time for absorption, binding to active sites Lead crosses the blood-brain barrier in young animals Excreted in milk Crosses the placenta (possibly resulting in abortion, brain damage)

paraquat therapy

• Early = emesis, charcoal, cathartics • *Bentonite preferred adsorbent (clay)*; superior to activated charcoal; if it's been 2 days, no use • Supportive care • Biochemical antagonists - Acetylcysteine, Superoxide dismutase (orgotein), ascorbic acid • Ventilation, respiratory support *(NO OXYGEN)* • Renal function - fluids for diuresis • Prognosis: hopeless if signs present

cholecalciferol lesions on necropsy

• Early: Renal tubular necrosis • Mineralization in kidney, heart, lung, stomach, intestine • Aortic plaques • Thyroid hypertrophy/hyperplasia • Renal cortex red-gray • Tubular necrosis, renal, arterial and cardiac mineralization microscopically

clinical pathology results of cholecalciferol intoxication

• Elevated Serum Calcium (> 12 mg/dL) • Elevated serum phosphorous(> 7 mg/dL SA) • Increased BUN and creatinine • Urine sp gr = hyposthenuria (1.002 - 1.006)

factors important in feed exposure

• Feed intake varies with species, size, age and production or work of animals. • Water intake is roughly twice the feed intake, by weight, but also varies with environmental conditions. • Rate of consumption Vs dilution with fiber or roughages

If Feed Concentration is gm/Ton - Convert to PPM

• First convert Ton in lbs → Kg • Then g → mg • 1gm/ton = 1000 mg ÷ (2000 lb ÷ 2.205 lb/kg) • =1000 mg ÷ 907 kg • = 1.102 mg/kg = 1.102 ppm....so • 1 gm/ton = 1.1 ppm (memorize)

Environmental and Food safety impact of Pyrethroids

• Fish are extremely sensitive!! - Shut off tank pump; cover air intake and tank during spaying or fogging in the home - Toxicity to other cold-blooded species?? • Birds considered relatively resistant - Exotic species - little safety information • Food safety: Fenvaleret, Cypermethrin, Flucythrinate, Permethrin residues of concern

Fipronil (1996)

• Flea and tick control on animals • Frontline® flea control • also as MaxForce FC® bait stations, Regent® on seed corn • *GABA inhibitor in insect-->excitation* • anecdotal toxicoses in dogs - unsubstantiated • Dx: confirm exposure; but toxic levels unknown

Why are Numbers Important?

• Fundamental to practice of medicine/toxicology • Calculation of Drug Dosages • Estimation of toxic dosage from foods or the environment • Interpretation of Toxicology data • Essential to estimate risk - Known exposures - Potential exposures

lead clinical signs in cattle

• GI - anorexia, *rumen stasis*, gaunt, salivation • *CNS - blindness, muscle twitching*, head bobbing, depression, *bruxism*, circling, *convulsions* • Acute convulsive death in calves o GI anorexia, rumen stasis, gaunt, salivation o CNS blindness, muscle twitching, head bobbing, depression, bruxism, circling, convulsions, acute convulsive death in calves

risk factors for anticoagulants

• Geriatric or neonatal animals • Concurrent liver disease • Ruminants, horses - Moldy sweet clover • Protein displacing drugs - Phenylbutazone - Sulfonamides - Also Corticosteroids, Aspirin ►Impaired platelet function or low counts but if any other condition affecting platelet count, could predispose animal to bleeding rodenticides tend to be bound by plasma proteins such as albumin so if concurrent exposure to drugs or meds that displace anticoagulants from albumin, have available free in circulation in active form--make animals more susceptible Highest morbidity and mortality in neonatal, geriatric and animals with pre-existing liver disease Warfarin is ~ 90% protein-bound (mostly to albumin) so substances or conditions that displace bound warfarin from albumin will release more free (active) drug into the plasma where it is transported to and concentrated in the liver. These include: o Drugs phenylbutazone sulfonamides diphenylhydantoin corticosteroids o Fatty acids high fat diet o Uremia may also slow excretion Substances or conditions that impair platelet function o Aspirin o Phenothiazines ACE o Antihistamines Decreased availability of Vitamin K o Prolonged use of antibiotics (decrease intestinal bacterial vitamin K synthesis) o Neonates typically are hypoprothrombinemic/vitamin K deficient

heavy metal oxidation states

• Heavy metals have multiple oxidation states. • - e.g. Common oxidation states of Se: -2, 0, +4, +6 • This leads to the formation of different compounds having different toxicologic properties.

clinical signs of paraquat toxicity

• High dose ..early - vomiting, ataxia, seizures • *Respiratory signs are delayed 2-7 days* - Tachypnea, dyspnea, moist rales • *Hypoxia*, cyanosis, pneumomediastinum; reduce pulmonary compliance, death by day 8 • Moderate exposures may die in 2-3 weeks • *Progressive, irreversible lesion* • Pulmonary radiography: mild lesions; bad if they present later because lung fibrosis has occurred-->poor gas exchange and hypoxia

diagnosis of amitraz

• History of exposure • Compatible clinical findings • Hyperglycemia may be suggestive • Chemical detection in stomach content, urine, feces, tissues, blood, skin • Detection only confirms exposure, may not correlate with severity of signs - no test like acetylcholinesterase test that can tell severity of exposure

lead diagnosis

• History,clinicalsigns • *Lead in whole blood* > 0.35 ppm (0.25 avian); normal = < 0.05 ppm • Lead in *kidney or liver* > 8 ppm; normal = < 0.5 ppm • *Radiography* - lead objects in gut (next 2 slides) History, clinical signs Lead in whole blood o > 0.35 ppm; normal = < 0.05 ppm Lead in kidney or liver o > 8 ppm; normal = < 0.5 ppm Radiograph o lead objects in gut Peripheral blood smear in dogs Ca-EDTA mobilization test Pathological Findings (dogs) o Increased nucleated RBCs and basophilic stippling without severe anemia is highly suggestive of lead poisoning in dogs Pathologic findings (cattle) o Few significant gross lesions o lead objects in rumen or stomach o rumen protozoa dead or inactive o laminar cortical necrosis (DDx from PEM) o inconsistent acidophilic intra-nuclear inclusions in renal tubules o porphyrinuria

pathophysiology of cholecalciferol intoxication

• Hypercalcemiaconduction dysfunction - Shortened Q-T segment and increased P-R - Bradycardia with increased heart sounds - Vasoconstriction and hypertension • Hyper-Ca-->reduces cAMP-->low ADH - Decreased NaCl absorption-->diuresis • Renal tubular degeneration-->polyuria and hyposthenuria Azotemia

Example: PPM in Feed vs BW dosage (mg/kg)

• If toxic dosage of arsenic (As) is 3 mg/kg BW and feed intake is 3% of BW, what feed concentration will provide this toxic dosage. • Setup: mg/kg BW = toxicity in mg/kg BW feed as % BW • Solution: mg As/kg BW = 3 mg/kg 0.03 = 100 ppm As in Feed

Estimating Exposure from Sprayed Chemicals in Grazing Animals

• Information Needed - Estimate of amount applied/acre - Estimate of yield per acre (amount forage carrying the applied spray) - Amount of forage consumed/day (dry wt basis) • Calculate spray/sq. ft • Calculate forage/sq. ft to get amount of spray/unit weight of forage • Use yield of 2 Tons forage/Acre and 1 lb Spray/Acre • 1 acre is ca. 44,000 sq. ft. & assume feed intake is 3% • 1 lb = 454g = 454,000mg ÷ 44,000 sq ft = 10.3 mg/sq ft • 2 tons x 907 kg/ton = 1814 kg ÷ 44,000 sq ft = 1,814,000 g ÷ 44,000 sq ft = 42 g forage/ sq ft. • 10.3 mg chemical/sq ft ÷ 42 g forage/sq ft = 0.245 mg/g forage • 0.245 mg/g x 1000 = 245 mg/kg = 245 ppm on forage • mg/kg BW = 245 ppm x 0.03(% BW eaten) = 7.35 mg/kg dosage (from spraying 1 lb on 1 acre land)

mechanism of OP's - carbamates

• Inhibit acetylcholinesterase at cholinergic synapses. • Allows for continuous stimulation by accumulated acetylcholine • Signs reflect stimulation of parasympathetic nervous system and neuromuscular junctions - cause cholinergic crisis -by inhibiting enzyme that breaks down acetylcholine, acetylcholine accumulates and causes stimulation of nerves; -OP: may become permanent bond; aging? -carbamates: bond with enzyme not that strong

selenium in the environoment

• Kesterson National Wildlife Refuge achieved national notoriety in 1983 when agricultural runoff was poisoning the area's birds. • Reduced fertility - Severe birth defects - in stilts, grebes, shovelers, coots, and other aquatic birds. Kesterson National Wildlife Refuge achieved national notoriety in 1983 when agricultural runoff was poisoning the area's birds. The naturally occurring element selenium was associated with falling fertility and severe birth defects in stilts, grebes, shovelers, coots, and other aquatic birds. Selenium, lead, boron, chromium, molybdenum, and numerous other contaminants were accumulating in refuge waters because the refuge had become an evaporation pond for tainted water draining from the region's fields. The flat valley floor is composed of ancient sea bed sediments that contain high levels of trace elements, heavy metals, and salts. Perforated pipes (tile drainage) buried in the fields drain away excess water—and with it dissolved salts and trace elements—after flood irrigation.

MANAGEMENT OF TOXICOSES

• Management of a poisoned animal is considered an emergency. Approach: *"Treat the patient not poison".* There is no cookbook approach as each patient is unique. But the general guideline is as follows: 1. *Stabilize Vital Signs* (Attend to the ABCs i.e. airway, breathing, and circulation to *keep the patient alive!*) 2. Get more Hx and re-evaluate the patient 3. Prevent further absorption 4. Give specific antidotes if available 5. Enhance elimination

bonding of heavy metals

• Many heavy metals form coordinate *covalent* bonds • *Sulfur*, oxygen and nitrogen bind to heavy metals through this type of bond. - Can be basis for toxicity - Example - heavy metals *can bind to S atom on proteins and inactivate the enzymes*

clinical effect of anticoagulants

• May be delayed 3 - 6 days after exposure • Related to hemorrhage and blood loss • Often weak, anemic, dyspnea, epistaxis, melena; lameness, ataxia • Occasional CNS signs (subdural bleeding) • Hemothorax (dyspnea, sudden death) • May be acute death with no early signs • Placental hemorrhageAbortion depending on where animal has bled, have clinical signs

diagnosis of OP's - carbamates poisoning

• Measure cholinesterase activity - in blood, brain, retina (refrigerate) - carbamates regenerate to normal [different cholinesterases exist] • Chemical analysis: - parent compound in rumen/stomach content, hair, suspect material: feed, spray, pour-on, -good blood marker -measuring cholinesterase activity quickest way; results in hours. -take whole blood - preferred to plasma; little activity in plasma -relying on integrity of sample. if sample compromised in anyway (sitting on bench or hot summer and animal autolyzed) then enzyme activity measurement won't work--get false positive. -do test same day for carbamates; if you keep refrigerated, not a problem for OP's -if it is typical OP or carbamate exposure, find enzyme suppressed 90% of the time. if you have 50%, not likely to e associated with clinical signs. if 50% in brain, conformity of OP or carbamate. in blood, enzyme measuring is psuedocholinesterase enzyme, the true one in CNS and nobody knows why we have pseudo version but it's good biomarker. true present in retina looking. 20% inhibitory in brain--not conclusive. taking rumen contents, environmental samples good way to confirm. -death comes quickly with these. plenty of OP compounds in feed, less in rumen contents. it all depends on exposure and how much time has passed. hair sample of choice if topically applied

Units of Measure

• Metric system is best approach (vs English system) • Be familiar with conversion factors from one unit of measure to another. • Kilogram is a standard unit of weight i.e. 1Kg/Kg =1,000 g/Kg x 1,000mg/g = 1,000,000 mg/Kg • Part per million (ppm) = 1a + 999,999b Thus, 1 mg/kg = 1 ppm (commit to memory) • 1μg x 1000 = 1mg x 1000 = 1 gm x 1000 = 1kg - Therefore, 1 ug/kg = 1 ppb • 1 ug x 1000= 1 mg x1000= 1 gm - Therefore 1μg/g = 1 ppm • 1 ng x 1000=1 ugx1000=1 mgx1000=1g - Therefore 1ng/g = 1 ppb

zinc phosphide toxicity

• More toxic when consumed with food • Gastric acid releasehydrolysis of bait • *Dogs 300 mg/kg (empty stomach);* • *Dogs 40 mg/kg taken with food* • Sheep LD50 is 60 mg/kg • Toxicity: birds (geese, pheasant) 7 - 10 mg/kg BW LD50 • Fish: LC50 is 0.5 - 1 mg/L

herbicides summary

• Most are selectively toxic to plants • Toxic if animals drink from buckets or sprayed • Arsenicals, chlorates, bipyridyl, dinitrophenols most toxic • 2,4-D enhances palatability of forage and increases risk to nitrate toxicosis • Wood preservative CCA hazard to livestock

toxicokinetics of chlorinated hydrocarbons

• Oral, topical, inhalation absorption (to major route--not volatile) • Lipid soluble - rapid absorption from skin • Distribute to liver, kidney, brain, fat; even within tissues they partition more into fatty components of tissue like liver, muscle, kidney • Metabolism by mixed function oxidases to more toxic epoxides (for cyclodienes) which cause oxidative stress • Accumulate in brain, fat; • Excreted in bile and milk fat because lipid soluble ; long half life due to recycling of bile in enterohepatic circulation • Released to blood during weight loss.; in winter in birds and other animals • Excretion half life may have two compartments...see next slide....

typical results for acute toxicosis of anticoagulants

• PCV < 30 • Whole Blood Clotting: delayed • Clot retraction: normal • ACT: 2-10 times normal • PT: 2-6 times normal • APTT: 2-4 times normal • Platelets: normal • FDP's: normal graph: takes several days to come back to normal

lead toxicity diagnosis

• Peripheral blood smear in dogs - Nucleated RBCs, basophilic stippling • Ca-EDTA mobilization test • Urinalysis: increased delta-aminolevulinic acid (ALA), lead levels

cholecalciferol intoxication causes

• Persistent hypercalcemia & hyperphosphatemia • Early renal tubular damage & necrosis • Abnormal soft tissue mineralization - renal tubules and small arterioles

factors affecting poisoning outcome; nutritional status

• Phase I and Phase II metabolism (conjugation) ○ Depend on nutrition § If animal deficient, may be more susceptible and therefore more susceptible to lower dosages of particular toxicants

sources of selenium

• Plants... reflect soil levels; - high in the western great plains N/S Dakota, Wyoming, Montana, Kansas Accumulated in arid, alkaline soils Nebraska, Alkali disease (chronic selenosis) was a significant economic threat in late 1800s - low in much of the midwest and eastern U.S. Plants... - Obligate accumulators...1- 1000 ppm (make Se bioavailable for crops) - Passive accumulators... ● crop plants, forages....< 50 ppm Se • Feed supplements (since 1973) - up to 0.3 ppm Se added to feed since 1987 - accidental "mis-mixes" of these Injectable Se products... - contain 1, 2.5, or 5 mg Se/ml along with 50 mg vitamin E - Most common acute selenium poisoning in lambs ..... injectable Se overdose

What is heavy metal?

• Poorly defined subset of elements that exhibit metallic properties • Relatively toxic (Pb, Sn, Hg, Tl, Au, Pt, Ba) • Considered "meaningless" by IUPAC

diagnosis of anticoagulant poisoning

• Presence of hemorrhagic syndrome • Clotting time prolonged • Prothrombin time (@ 2-3 days) post exposure • Activated partial thromboplastin time (@ 3-5 da) • PIVKA - Proteins Induced by Vit K Antagonists (a.k.a. Thrombotest) detects precursor proteins of clotting factors • Detection of active ingredient in liver, blood, bait • Liver: sample of choice in deceased animals • Blood: Sample of choice in live animals; not uncommon to get false positive. Takes a while before animal bleeds. Healthy animal: could have false negative • Hay: for dicoumarol

2. *decontamination*

• Protect staff from exposure • Reduce further absorption - Removal of / from source (dermal, oral) • *Empty stomach ...emetics -Most effective @ < 1 hr*

Long History of Insect Control

• Pyrethrins (Chrysanthemum spp) since 1500s • Nicotine - 18th century • Cyanide, Lead arsenate - 19th century • Rotenone • OP & Carbamates products - 1944: leading group of insecticides being used • DDT - 1945 ALL ABOVE - HIGHLY TOXIC, NON- SPECIFIC

specimen selection

• Requires good knowledge of absorption, - metabolism, - excretion and - half-life of the toxicant. • The *ideal tissue sample* (sample of choice) is one which *contains the highest amount of toxicant* at collection time.

factors affecting poisoning outcome: route of exposure

• Route of exposure: ○ Non-lipid soluble: can only be absorbed orally • All routes of exposure important ○ IV ○ IM ○ Inhalation ○ Etc. Most exposure oral and through skin

Environmental and Food safety impact of Amitraz

• Several animal species are targets • Minimal relay toxicosis • Food safety impact ????

factors affecting poisoning outcome: solubility e.g. barium sulfate vs. barium chloride

• Solubility: some salts toxic compared to others ○ Barium sulfate: can be used for imaging of GIT; not absorbed Barium chloride: very soluble; water soluble; well-absorbed and cardiotoxic

anticoagulant treatment

• Supportive - Relieve hemothorax, raise PCV, Rx Shock • Vitamin K 1 (Vit K3 is ineffective) - oral route with fatty food preferred (not IV) - 3-5 mg/kg/d - 3-5 mg/kg/d - 5 mg/kg/d - Horses 2mg/kg/d maximum (warfarin for 10 days) (2 - 4 weeks for brodifacoum) (3 - 4 weeks for diphacinone) • Time lag 3 - 6+ hrs for effective coagulation. Check to make sure you don't need to increase vitamin K dose. • Blood or plasma transfusion-> for immediate clotting factors • Continue to monitor clotting function (PT) for 1 week after therapy stops if jumping around, will bruise

treatment of chlorinated hydrocarbon

• Symptomatic: *Control seizures*, supportive care (diazepam, phenobarb, pentobarb, muscle relaxants) • Activated charcoal if oral ingestion, cathartics; reach from intralipid drug but no specific antidote • Dermal...wash with soap and water -control hyperthermia -if topical, hose them down with proper PPE

overdose of selenium was cause of deaths of 21polo horses in Florida Fall of 2009

• Test results showed that the animals had 10 to 15 times the amount of selenium in their blood than normal and 10-20 times the normal amount in their liver • Franck's Pharmacy of Ocala, Fla. - "the strength of an ingredient in the medication was incorrect."

clinical signs

• Very important in reaching a diagnosis. Note: Keep Hx in perspective for dd • Pay attention to detail - Many toxicants will likely cause similar clinical signs. - Look for pathognomonic clinical signs e.g.. pinpoint pupils in carbamate poisoning; - Remember you are seeing a "snap shot" in a chain of events C) Determine time of clinical onset relative to exposure i.e. is this an acute onset following recent exposure or did clinical signs worsen over a long time period? • D) How long is the duration of disease from onset to death? • E) Determine Pathophysiologic effects-- Clinical chemistries, Acetylcholinesterase tests, renal or other biological markers, etc - *Take blood and urine samples first thing!*

added therapy for anticoagulant poisoning

• Vitamin K3 (menadione) may be useful as preventive - not therapy; not as effective because has to be metabolized to active form • Avoid K3 in horses - Nephrotoxic • Ruminants - 0.5 - 1.5 mg/kg SID IM or SQ sequelae of bleeding: hypoxia that could effect liver function-->vitamin K 3 won't work well.

lead poisoning most frequent in

• cattle • dogs • cats, pet birds, zoo animals • sporadically horse, sheep • waterfowl & raptors • pigs resistant Species affected o Dogs o Cattle o Cats, pet birds, zoo animals o Horses and sheep (sporadic) o Swine (typically resistant) o Wildlife, waterfowl and raptors

inorganic arsenic lesions

• g.i. hemorrhage, edema, fluid filled • sloughing mucosa • renal tubular degeneration

necropsy lesions of anticoagulants

• hemorrhages, hematomas, hemothorax • hemarthrosis; subdural hematomas • occur in a variety of tissues, organs, spaces • platelet function normal

diagnosis of iron toxicity

• history, clinical signs • abdominal radiograph... mass of pills in stomach • Serum iron... • - normal... 80 - 240 ug/dL - if 300 - 500... monitor closely - *if >500...chelation therapy* • Serum total iron binding capacity (TIBC)- If serum iron >TIBC = poisoning likely

Concentration in Body Fluids

• ppm vs mg/100 ml = mg% = mg/dL • 1 ppm is 1 mg/1000 ml • 1 mg/100 ml = 1mg x (1000 ml ÷ 100 ml) • = 1 mg x 10 = 10 mg/ml = 10 ppm • Thus 1 mg/dL = 10 mg/L = 10 ppm.....and • 1 ppm = 0.1 mg/dL and 1mg/dL = 10 ppm - Multiply by 10 to convert mg/dL to ppm - Divide by 10 to convert ppm to mg/dL

Zinc/Aluminum phosphide as anticoagulant

• rodenticide, 2 - 5 % in baits • limited use, alternative to anticoagulants • gray-black powder, 76 % zinc • decomposes in acid or moist environment • Odor is attractive to rodents • Wild turkeys not bothered by odor • *Secondary poisoning rare but possible* • Allowed to be baited in apples, grains, bread, vegetables • *More toxic in animals that have recently eaten*

Zinc phosphide: Treatment

•Detox/Symptomatic/Supportive • Activated charcoal, cathartics • Antacids in stomach - raise pH > 5 • Combat acidosis, hypocalcemia, liver damage • B vitamins, glucose for possible liver damage • Demulcents, protectants for GI irritation • Prognosis: Guarded Prevention • Proper baiting technique • owner education

diagnosis of nicotine toxicity

►History of exposure ►Clinical signs (SLUDD) ►Chemical analysis for nicotine in urine, vomitus, liver, kidney, blood/serum; could take any of these chemicals for analysis; very important to take samples; tell clients to bring in vomit

bromethalin mechanism

►Metabolized to desmethylbromethalin - Parent and metabolite Uncouple oxidative phosphorylation especially in CNS ►Billiary excretion - Reduced ATP impairs sodium pump & leads to fluid accumulation in myelin sheaths and CNS - Edema of myelin tracts leads to paralysis o Bromethaline interferes with mitochondrial energy production especially in the CNS o Oxidative phosphorylation is uncoupled which decreases intracellular ATP concentrations via decreased ATP'ase activity. The Na+/K+ pump fails resulting in intracellular edema and electrolyte imbalances within the brain parenchyma o Lipid peroxidation of myelin also occurs o Increased intracranial pressure follows

ideal drugs/toxicants for forced diuresis with pH manipulation have:

►low protein binding properties, - limited metabolism, - high renal clearance, - small volumes of distribution (primarily in extracellular fluid), and - their pKa must be in such a range that maximal renal excretion can be achieved by realistic alteration of urine pH. *The pKa of drugs is included on drug inserts.*

amitrax

● Formamidine insecticide - topical for controlling ticks, keds, lice and mites Mitaban - for topical use on dogs Taktic - mites, lice, ticks on livestock Preventic - collars for dog tick control ...dogs poisoned by ingesting these collars Collars are 9% Amitraz, weigh 27.5 g = mg. active ingredient? 2.5 grams (2,500 mg); if you have 10 kg dog, dosage would be: 250 mg/kg BW; toxic oral dose is low. easily problematic.

clinical signs of bromethalin poisoning

● Lower doses (field cases), onset @ 24 - 86 hrs - tremors - ataxia - vomiting+ - anisocoria - progressive depression - hind limb paralysis - lateral recumbency - coma ● Higher doses (SupraLD50) onset in 4 - 36 hrs muscle tremors, convulsions, hyperexcitability, running fits, hyperesthesia, focal or generalized motor seizures precipitated by light or noise. No gender or breed dilection Risk factors o none in particular Historical findings o signs and observations often reported by the owner Interactions with Drugs, Nutrients, or Environment o Relay toxicity possible Signs are almost always referable to the brain, the primary organ affected o May see signs of toxicity in as little as 3-4 hours after doses above the LD50 (in experimental conditions) seizures (often externally provoked) severe muscle tremors running fits extreme excitability hyperthermia o In sublethal doses (field poisonings) there is a slower (24-86 hours) and dose- dependent onset of signs impaired conscious proprioception hindlimb ataxia to paralysis depression to coma anisocoria opisthotonos o +/- vomiting o forelimb extensor rigidity or other posturing o fine tremors o lateral recumbency Signs are variable and dose dependent

other sources of vitamin D3

●Calcipotriene (Dovonex® psoriasis lotion) is very toxic and high risk to dogs. - Dovonex is a congener of 1,25 dihydroxy D3 -readily available without activation so clinical signs manifest within hours ►Vitamin Supplements • Vitamin D feed supplement errors ►D3 is 10X more potent than D2 for Ca uptake ►Toxic plants (S. malacoxylon, C.diurnum, T. flavescens)

Diagnosis and Treatment for Starlicide

●Look for Starlicide - Stomach/crop contents - Liver and kidney ●Histopathology Tubular necrosis of epithelial cells ►Treatment: Supportive ►Prognosis: Guarded