Toxicology - reviewed

Define toxicology and why we study it?

Toxicology = the study of adverse effects of xenobiotics. Outlines the identification and characteristics of poisons, their physical + chemical properties, fate in the body (absorption, distribution, metabolism, excretion), their biological effects and treatment.

• animal welfare - prevention and treatment

• economics - prevent or reduce effects

• ecosystem health - pollutants disturbing ecological balance

• implications in human health

Define xenobiotic, poison, toxin, venom, toxicity and toxicosis

Xenobiotic = chemical found in an organism that is not expected to be present in the body (not necessarily bad)

Poison = a xenobiotic substance that after contacted or entered the body (any route, and reach an active site) in sufficient quantity will cause a detrimental effect in an organism (the dose makes the poison!)

Toxin / Toxicant = a poison of biological origin

Venom = a xenobiotic of biological origin that is injected via a bite, sting or sharp body part to exert detrimental effects

Toxicity = a measure of the harmfulness of a xenobiotic

Toxicosis / Intoxication / Poisoning = syndrome or condition of adverse health effects caused by exposure to a toxicant

Define a hazard vs a risk

Risk = a situation that increases the probability of injury or loss

Hazard = the potential of an agent under define conditions of exposure to cause an adverse effect

• to be hazards, it must be toxic AND:

  • likely to be encountered and in a form that can be assimilated

  • likely to be consumed in sufficient amounts to cause harm

  • reach a site within the body, requiring uptake/transport

  • interact with metabolic pathways

• not likely to cause poisoning even though they may be highly toxic

  • unlikely to be encountered by animals in any forms

  • exist in a form which cannot be assimilated

  • need large volumes, high unpalatable or emetic at sub-lethal doses

Explain biotransformation and bioactivation

Biotransformation = the process of metabolism of a xenobiotic in order for it to be neutralised and excreted from the body

• The liver is most common organ, however also occurs in kidneys and lungs

• site of biotransformation varies with species and xenobiotic

Bioactivation = the process by which a xenobiotic becomes more toxic after metabolism. This site/organ shows the most damage.

Explain induction

Induction = metabolic enzymes that break down toxins have the capacity for up-regulation if increased amount of substrate encountered

• exposure to the same or a chemically similar compound will cause adaption and increased resistance to xenobiotic load

• usually a good think, liver can safely handle more

• once demand decreases, the enzyme (Cytochrome p450 or CYPs) that has increased drops back to ‘normal’ levels

• may be detrimental if xenobiotic is rapidly metabolised and produces an excess of toxic metabolite (via bioactivation) in higher local concentrations

• may be detrimental if CYP induction to one compound impacts the toxicity of an incidental/unrelated compound, due to being metabolised by the same pathway

Define resistance vs tolerance and their mechanisms

Resistance = an innate property, developed by natural selection and evolution, thus possessed by all members of the species

• enhanced hepatic excretion (endogenous biotransformation)

• gut microflora modify compounds (exogenous biotransformation)

• modify or circumvention biochemical pathways vulnerable to the toxin

Tolerance = an acquired trait of an individual to be resistant to a normal toxic dose of a xenobiotic.

• induction of CYP’s

• altered kinetics

What are the pathophysiological mechanisms of toxicity?

Target Organ/s = those organs showing the most toxicity in the animal

• organ closest where xenobiotic enters body (intestine/liver)

• site of concentration (kidney)

• site of metabolism + bioactivation (liver, lung, kidney)

Toxins function at a cellular level:

• energy supply (heart + brain mostly)

• membrane integrity or function

• inhibition of an enzyme / metabolic pathway - competition for substrate / irreversibly binding active site

  • Antimetabolite = successfully replace normal enzyme substrate

• DNA damage (mutations → cancer→ cell death)

Paracetamol / Acetaminophen

• Cats lack glucuronyl transferase enzyme pathways to metabolise and excrete it

• metabolism is shunted to oxidation pathways = lots of free radicals → cell membrane damage

• toxic effects to liver and blood

  • methemoglobinemia (brown blood) + Heinz body formation in RBC → haemolytic anaemia = asphyxiate with low blood O2 carrying capacity

  • liver/hepatic necrosis due to site of metabolism → bioactivation = cell death

• Clinical Signs

  • brown + clumped blood

  • cytotoxic MM (blue) or jaundice

  • face and paw swelling/subcutaneous oedema

  • depression vocalisations

  • vomiting → anorexia

• Treatment

  • prevent absorption = emesis, activated charcoal, gastric lavage

  • antidote = N-acetylcysteine (restore cellular stress)

  • ascorbic acid + methylene blue = reduce methaemoglobin → haemoglobin

  • supportive care

Define acute vs chronic toxicity

Acute = exposure causes clinical effects and/or death in mins-hours

Chronic = long term exposure (signs are often acute), harder to manage as it may be unknown until its too late

Define the threshold dose and an a cumulative poision

Threshold dose = dose where clinical signs or adverse effects appear

• most toxic the substance = closer the threshold dose is to 0

• usually sigmoidal in shape

• if the substance does not accumulate, the sub-threshold dose may be given repeatedly with no effect (successfully metabolise and excrete)

Cumulative Poison = small amounts accumulate until they reach the threshold at which signs being to appear

How to diagnose and recognise toxicities?

• Peracute conditions = may be no lesions or clinical signs

  • Clinical signs often associated to disfunction of an organ

  • Sudden death → autopsy

• Residues of toxins are small due to rapid metabolism = hard/impossible to detect

• Toxin assays are expensive - usually just predict/assume

• Detailed questions to owners

• Examine animals environment

How can you treat toxicities?

• often rapid death

• Antidote = a substance that is given to specifically counteract a poison (neutralise it and reverse)

  • react and neutralise toxin (anti-venom for snake bites and tick)

  • competitive inhibition (ethyl alcohol if ethylene glycol/antifreeze ingested)

  • chelates toxin and forms insoluble/inert compound = prevents reacting with sensitive molecules (EDTA)

  • vitamin K injectection to counter anticoagulant of rat poison

• reduce / prevent further exposure

  • purgatives / emetics = induce vomiting to remove from GIT (apomorphine or salt)

  • washing = remove excess from skin / MM

  • pressure bandage = limit spread of venom

  • absorbents = minimise or prevent uptake from GIT (charcoal)

  • cathartics = increase rapid GIT passage/diarrhoea

• supportive care and symptomatic treatment

  • anticonvulsants

  • analgesic

  • fluids = dilute

  • oxygen = dilute and support resp

  • nutrition

  • cooling

Chocolate

• pancreatitis a few days post ingestion to high fat content

• pulmonary oedema lesions due to acute heart failure

• cardiomyopathy / sudden death due to theobromine

  • exercise → tachycardia

  • cyanosis

  • terminal convulsions

Anticoagulant Rodenticides - Fluoroacetate and Bromethalin

• primary poisoning = ingredient in baited poisoning

• secondary poisoning = contaminated carcasses

• 0.5-2hrs between ingestion to toxin onset/clinic signs

  • initial hyperirritability + restlessness

  • GIT hyperactivity (vomiting + diarrhoea + urinating)

  • dyspnoea (hard to breath) + frothing at mouth/nose

  • wild running, hysteria and barking

  • Anaemia and haemorrhage

  • CNS disturbance (convulsions + paddling)

  • opisthotonos (back flexion + extensor rigidity)

  • increased body temp

  • sudden death between 2-12 hours

Treatment:

• poor prognosis

• Fluoroacetate: provide acetate ions to prevent conversion of fluoroacetate to fluorocitrate OR barbiturate anaesthesia + ‘antidotes’ like glyceryl monoacetin, acetate ions to electrolyte solution + sodium bicarbonate

• anticoagulant rodenticide: exogenous Vitamin K1

• bromethalin: diuretic to reduce brain swelling

Bufo marinus Toads

• susceptible = mammals, birds and reptiles (not chickens)

• cardioactive steroid = death from x1 exposure

• clinical signs:

  • buccal irritation

  • profuse salivation with head shaking + pawing at mouth

  • hyperaemia of buccal mucosa

  • vomiting + diarrhoea (haemorrhagic)

  • ataxia + weakness

  • cardiac arrhythmia

  • polypnoea (rapid/irregular respiration)

  • convulsive seizures

  • sudden death (within 15mins)

Treatment:

• good prognosis if mild but can be poor-severe

• scrub gums (poison is sticky) with water

• control salivation + bronchoconstriction with atropine

• control seizures with diazepam

• support cardiac arrhythmias with oxygen

• wash with activated charcoal

Snake Bites

• owners rarely see the snake, and the bite is often hidden

• different snake venom = different signs

• dead snake fangs can also produce venom!

Tiger Snake

• neurologic, myolytic (muscle tissue)

• intravascular coagulation

• cardiovascular collapse → paralysis → sudden death

• Treatment = tiger snake antivenom

Common/Eastern Brown Snake

• paralytic syndromes

• hypocoagulability + haemodynamic collapse → hypotension

• sudden death

• Treatment = brown snake antivenom

Black Snake - Red Belly Black + King Brown

• destroys skeletal muscle → weak and paralytic

• myoglobinuria (red urine) and haemolysis (anaemia)

• Treatment = black snake antivenom (can also use tiger snake = cheaper)

Theraphosid (tarantula) Spider Bite

• only dogs are effected

• neurotoxic

• flaccid → paralysis → sudden death (in all dogs bitten)

• Treatment = none

Carbamates and Organophosphates

Conditions of Poisoning

• Insecticides and acaricides (often bright blue pellets)

• accidental treatment in home gardens OR malicious poisoning

• effects dogs and cats

Mode of action

• inhibits acetylcholinesterase enzyme → acetylcholine accumulates at nerve synapses → overstimulation of parasympathetic nervous system

• more dangerous as permanent bond, carbamates shorter half life and non-permanent bond = less harmful

Clinical Signs

• muscarinic = constricted pupils, salivation, diarrhoea, bronchoconstriction → dyspnoea, bradycardia, lacrimation (tearing)

• nicotinic = involuntary twitching

• CNS = convulsions, coma, tremor, weakness, restlessness

• Diagnosis = blue dye in vomit, faeces etc

Treatment

• Atropine = blocks excess acetylcholine effects

• Oxime (antidote) = hydrolysis the phosphorylated acetylcholinesterase enzyme

• Nursing = wash skin, induce vomiting, activated charcoal

Metaldehyde

Conditions of Poisoning

• Molluscicide (often bright green pellets)

• accidental treatment in home gardens OR malicious poisoning

• effects dogs cats, horses, cattle, sheep, poultry, parrots, children

Mode of action

• rapid hydrolysis in stomach → acetaldehyde → rapid absorption to liver + oxidation

• acetaldehyde crosses blood brain barrier → blocks GABA inhibitory neurotransmitters → increase monoamine oxidase = nervous system

Clinical Signs

• onset = minutes-hours after ingestion

• anxiety + depression

• hypersalivation + vomiting + diarrhoea (green dye)

• incoordination, muscle tremors, and convulsions → opisthotonos

• hyperthermia

• tachycardia, tachypnoea and dyspnoea

Treatment

• Reduce exposure = emetics, gastric lavage, enema

• Control seizures with muscle relaxants and anticonvulsants

• Cool for hyperthermia

• Nursing = IV fluids, correct acid-base, monitor renal function

Brunfelsia spp

• Fruits and flowers are very fragrant to dogs

• Method of Action = brunfelsamidine → nervous system

• Clinical Signs

  • GIT upset (vomiting, diarrhoea and urination)

  • ataxia

  • muscle tremors

  • convulsions → opisthotonos + extensor rigidity

• Treatment = emetics, activated charcoal and anti-convulsant

Strychnine

Conditions

• vertebrate pesticide to kill rodents and dingo/coyote

• primary effects cattle, sheep, horses, pigs, dogs, cats, rats

• secondary effects pets, birds of prey eating carcasses

• malicious poisoning (illegal in QLD)

Mode of Action

• blocks central inhibition of motors neurons

• uncontrolled, stops all reflexes

• symmetrical rigidity + tetanic convulsions (nervous system)

Clinical Symptoms

• onset = 10-30 mins post ingestion

• apprehension, nervousness, tense

• induced/oversensitive to stimuli

• muscle rigidity → tetanic spasms

• pupil dilation

• cyanosis (blue MM)

Treatment

• if untreated, death in 1hr

Duranta erecta “Geisha Girl”

• common garden plant with fruit or hedge shrub

  • low toxicity, requires large volumes

• effects dogs, cats, birds, cattle, kangaroos,

• Clinical signs

  • depression,

Synthetic Pyrethroids

• effects = mostly cats but also dogs, insects, crustaceans, fish, birds

  • in dog “spot on” treatments, so cats then rub up against dogs

• Mode of action = interfere with ion channels in axonal membranes and neurotransmitter levels (nervous system)

• Clinical Signs

  • onset within hours

  • tremors + seizures

  • excess salivation

  • ataxia + incoordination

  • hyperthermia

  • mydriasis

  • death

• Treatment

  • good prognosis

  • reduce exposure = emetics, gastric lavage, enemas, washing

  • supportive care = IV fluids, correct acid-base, warm

Macrocyclic Lactones

• anthelmintic and insecticide/acaricide

• effects dogs and cats, also cattle and horse

  • breed and younger animals more susceptible

• Mode of Action = GABA agonist, interfere with neurotransmission, increase GABA release, decrease nerve transmission → paralysis (nervous system)

• Clinical Signs

  • signs within 2 days of dosing, recover within 4-5 days

  • mild ataxia + recumbency

  • depression

  • hypersalivation but anorexia

  • mydriasis OR miosis

  • tremors

  • seizures uncommon

• Treatment

  • good prognosis

  • reduce exposure = emetics, gastric lavage, enemas, washing

  • supportive care = IV fluids, correct acid-base, warm

  • control seiu

Macadamia Kernels

• effects dogs

• Clinical Signs

  • hind leg weakness (nervous system)

  • ataxia + muscle tremors

  • depression

  • recumbency

  • joint pain and swelling

  • vomiting

  • hyperthermia

• Treatment = supportive care → recover in 12-24 hours

Cannabis

• illicit drug, cultivated plant

• effects dogs cats and ruminants

• Mode of action = binds to cannabinoid receptors in regions of CNS (nervous system)

• Clinical Signs

  • signs last 36-48 hours

  • depression

  • incoordination / sudden falling

  • dilated pupils

  • hallucinations

  • death is unlikely

• Treatment

  • emesis, activated charcoal - leaves seen in vomit

  • keep warm, dry, dark and quiet

  • if hyperexcitable, use sedatives with extreme caution

Barbiturates

• human medication but also could be in the carcase of an animal euthanised

  • remain active in carcasses for 6-8 months after burial/burning)

• effects dogs and birds of prey

• Mode of action = GABA like action, inhibit neurotransmitters → coma → death (nervous system)

• Clinical signs

  • liver and skeletal muscle

  • depression

  • slow resp rate and tachycardia

  • hyperthermia

  • hypotension

  • coma → death

• Treatment = O2 and ventilation, warming, IV fluids

Xylitol

• artificial sweetener in breath mints and baking

• Mode of Action = mimics sugar so makes pancreas release insulin → severe hypoglycaemia ± liver failure

• Clinical Signs =

  • incoordination + weakness

  • depression

  • lethargy + jaundice

  • tremors + seizures (nervous system)

• Treatment = glucose replacement + fluids (poor prognosis)

Amatoxins, Aflatoxins and Cycads

• Amatoxins = mushrooms

  • Mode of action = inhibit RNA polymerase II → interfere transcription + protein synthesis → cell death in liver

• Aflatoxins = mouldy food / garbage

  • Mode of action = inhibit cell division and hepatocellular regeneration in liver

• Cycads = dogs eating fern

  • Mode of Action = hepatotoxin → metabolised in liver

• Clinical Signs

  • immunosuppressant and carcinogenesis over time

  • gastroenteritis + diarrhoea → anorexia

  • hypoglycaemia

  • lethargy

  • liver failure = haemorrhage, jaundice, hepatic encephalopathy

  • death

• Treatment = O2, transfusions and coagulation support

Paraquat and PTFE (Polytetrafluorethylene = teflon)

• Paraquat = herbicide (dogs and cats mainly)

  • Mode of action = destroyed lung tissue via free radicals

• PTFE = teflon on cooking utensils / heat lamps (birds mainly)

  • Mode of action = acidic fumes damage lung epithelium

• Clinical Signs

  • vomiting and diarrhoea

  • dyspnoea, weakness, ataxia → resp failure

  • death

• Treatment

  • poor prognosis

  • do NOT O2 therapy

  • gastric lavage

  • emesis via activated charcoal

  • diuretics promote excretion

Ethylene Glycol (Anti-freeze)

• mainly dogs and cats - tastes sweet

  • melamine also causes similar acute renal tubular necrosis

• Clinical signs

  • CNS effects = “drunk”, euphoria, hypothermia, ataxia, weakness

  • GI effects = anorexia + vomiting

  • Increase plasma osmolality = thirsty and large urine output

  • dehydration = increase PCV and TP

  • renal azotaemia = increase urea, creatine, P, K but low Cl

  • hypocalcaemia

  • low blood PH = acidosis

  • abdominal / kidney pain = renal failure

  • coma → death within 12-36 hours

• Treatment

  • good prognosis if rapid intervention

    • reduce exposure = emetics, activated charcoal

    • reduce metabolism = antidote of vodka!

    • correct acidosis with sodium bicarbonate

    • large fluid therapy

  • poor prognosis if 30+ hour exposure

    • tubular necrosis and crystals on histopathology

Overdose of NSAIDs

• cats with aspirin = GIT ulceration and anaemia with Heinz body

• dogs that have ibuprofen = acute renal tubular necrosis and GIT ulceration

• horses that have phenylbutazone = acute renal tubular necrosis and GIT ulceration

• Clinical symptoms

  • inhibit platelet aggregation

  • restrict blood flow to gastric mucosa

  • conjugate in liver → excrete in urine

  • vomiting (± blood) → anorexia

  • melaena (bloody faeces)

  • hepatic and renal failure

• Treatment

  • reduce absorption = emetics, activated charcoal or gastric lavage, osmotic cathartics

  • fluid therapy

  • gastric protectants and counter metabolic acidosis

  • blood transfusions

Liliaceae / Lilly Flowers

• cats only

• Clinical symptoms

  • within 2 hours

  • anuria (no urine) → poor prognosis

  • polyurea (lots of urine)

  • increase serum urea, creatinine

• Treatment

  • emetics - activated charcoal

  • cathartic

  • fluid diuresis / renal support

Grapes and raisins

• dogs only

• Clinical symptoms

  • vomiting and diarrhoea within 2 hours

  • acute renal failure within 48 hours

Allium spp (Onions and Garlic)

• effects cats and dogs

• Clinical Signs

  • Heinz body anaemia

  • Haemolysis

Vitamin A / Retinol

• effects sheep liver and cats

• Carrots are very rich in vitamin A

• Clinical Signs

  • irritable, apprehensive, resent handling

  • lameness

  • loss of incisor / molars, gingivitis

  • rigid posture “Pointable cat” = spine freezing together

  • effects bone and muscles

Oxalate Raphide Crystals

• popular ornamental and house plants

• toxic to herbivores, cats, dogs, humans

• Mode of action = local mechanical irritation to buccal muscosa

• Clinical Signs

  • congestion ± swelling of buccal mucosa and tongue

  • increased salivation or drooling

  • pain → pawing at mount

• Treatment = anti-inflammatories to control pain + discomfort