Toxicology intro Flashcards
Toxicology
The study of the adverse effects of xenobiotic compounds (toxins and/or toxicants), including their chemical properties, biological effects and treatments
poison
Any substance capable of causing a deleterious response in a biological system
toxin
A poisonous substance that is a specific product of the metabolic activities of a living organism
* Antigenic poison or venom of plant or animal origin
* Subset of toxicants
dose
Amount of drug, toxin or toxicant that reaches the site or sites of action in an animal
ED50
Dose producing a therapeutic response in 50% of the population
effective dose
LD50
Dose causing death in 50% of the population
LC50
Concentration of a toxin/toxicant that will cause death in 50% of the population
We use these values to compare relative toxicities and estimate potency
bromethalin
rodentacide
uncouples ox phos, cells accumulate Na+, cells swell
neurotoxicity (cerebral and spinal cord edema) > paralysis
selenium deficiency
white muscle dz > cardiomypathy > death
skel muscle cannot sequester Ca2> calcification of tissue
selenium toxicity
Lethargy, tachycardia, sweating, teeth grinding
Hair loss, nail discoloration, hoof lesions lameness, emaciation, death
Zinc deficiency
Zinc-responsive dermatitis
* Alopecia
* Susceptible to skin infections
zinc toxicity
Intravascular hemolysis
GI irritation
Hemoglobinuria
Hematuria
penny ingestion
acute exposure
Exposure to a chemical for less than 24 hours
Usually a single dose occurring from a single incident
Death
ex:
* Iron overdoses in pigs
* Insecticide ingestion in animals
subacute exposure
Exposure to a chemical for one month or less
Repeated doses
ex:
* Dogs eating aflatoxin contaminated food for 4 weeks
Subchronic Exposure
Exposure to a chemical for 1 to 3 months
Repeated doses
ex: copper toxicity in sheep/dogs
Chronic Exposure
Exposure to a chemical for > 3 months to years
Repeated doses
ex: copper toxicity in sheep and dogs
aflatoxins
acute/subacute exposure
Ingestion of contaminated food (produced by fungus)
binds to hepatic proteins: hepatotoxicity
dogs, poultry most effected
routes of exposure
- oral
- dermal
- inhalation
- paraenteral (IV, IP, IM, SQ)
oral ingestion
Most common route of exposure in veterinary toxicology
Requires nearly all of the dose to pass through liver before reaching systemic circulation
dermal route of exposure
topical, percutaneous
flea spray, using dog flea products on cats
inhalation route of exposure
Lungs have large surface area, increased absorption
Avoids liver first pass effect
* Metabolism can occur in lungs (P450 enzymes)
birds very sensitive
Why are birds sensitive to inhalation?
Highly efficient at exchanging gases for high oxygen delivery to muscles for flight
High metabolic rates, small size
The air breathed is rapidly distributed to tissues
absorption
Process by which toxins/toxicants cross membranes and enter the bloodstream
affected by:
* solubility
* ionization (unionized= lipid soluable)
weak acids= unionized (absorbed) in stomach
weak bases= unionized (absorbed) in intestines
* ruminant vs monogastric
* Gastric motility, secretion, and the rate of gastric emptying
ruminants vs monogastrics absorption
Intake of nitrate and conversion to nitrite exceed microflora’s capacity to reduce nitrite
ruminants have different stomach compartments with different pH
dermal route of absorption
Lipid-soluble compounds well-absorbed
Formulation in solvents can facilitate absorption
distribution
When a drug or toxin/toxicant enters into systemic circulation by absorption, it gets distributedinto the body’s tissues
Depends on several things:
* Perfusion/blood flow through tissues
* Protein binding of drug
* Acidic drugs may bind protein and remain in circulation > low volume of distribution
* Basic drugs tend not to bind protein and are extensively taken up by tissues > larger volume of distribution
distribution via bloodstream
Portal blood circulation > Liver
Poisons/drugs not equally distributed throughout body
* Tend to accumulate in specific tissues/fluids
Blood-brain barrier tends to exclude hydrophilic poisons/drugs
distribution in blood brain barrier
Blood-brain barrier tends to exclude hydrophilic poisons/drugs
Younger animals more at risk due to immature BBB
ex: Lead poisoning in kittens – vertical nystagmus; muscle tremors/seizures
ivermectin toxicity
collie breeds
Deficient in multi-drug resistance gene (MDR1) > P-glycoprotein
* P-glycoprotein functions as an efflux drug transport pump at the blood-brain barrier
* Ivermectin cannot be transported out of the brain in MDR1 deficient animals > acts as a GABA agonist
Drug accumulates in brain causing CNS depression
Ataxia, CNS depression, mydriasis
lead toxicity
GI irritant, neurotoxicant (V/D, blindness, nystagmus)
Liver and kidney damage
Blood > Liver, Kidney, Brain > Bone
metabolism
Conversion of lipophilic toxins/toxicants > hydrophilic chemicals
* Inactivate (detoxify) xenobiotic agent
* Activate xenobiotic agent to pharmacologically active metabolite
metabolism phase 1 reaction
Functionalization reactions
Converts xenobiotic to a more polar metabolite through hydrolysis, reduction, or oxidation
In some cases, makes it more amenable to phase II biotransformation
May metabolize a xenobiotic agent to a toxic metabolite
metabolism phase II reaction
Conjugation reactions
Conjugation of large, polar molecule to render xenobiotic hydrophilic for excretion
Does not always result in less toxicity or inactivation
Methemoglobinemia
oxidative damage
tylenol
Cats have low methemoglobin reductase on RBCs
hepatotoxicity
excretion
Kidneys > Urine
Bile > Feces
Milk
milk excretion
Milk of cows tends to be slightly acidic + milk fat
pH 6.5 to 6.9 (relative to plasma – 7.2 to 7.4)
* Tends to concentrate basic, fat soluble toxicants/drugs
* Relay in toxicants to nursing calves, humans
excretion ion trapping
Altering the urine pH to inhibit reabsorption of toxicants across the renal tubular membranes into the blood stream
To “trap” the toxicants in its ionized form in the urine so it will be excreted
Non-ionized toxicants can diffuse across cell membranes because of their lipid solubility; whereas ionized molecules cannot diffuse across lipid membranes
chocolate toxicity in dogs
adenosine
* calming, vasodilation, prepare for sleep
caffeine, theobromine, theophylline (in chocolate)
* Inhibit adenosine and increase catecholamine release resulting in CNS stimulation, tachycardia, diuresis, smooth muscle contraction, vasoconstriction
* Cause release of dopamine and glutamate > excitatory neurotransmitters
Why are dogs predisposed?
* Long half-life of theobromine in dogs!
* Theobromine is metabolized into xanthine > methyluric acid by hepatic CYP450
age affecting toxicity
Younger animals
* Blood brain barrier still immature – more permeable than adult
* GI motility immature
* Lower glomerular filtration rate
* Rumen microflora low
Older animals
* Decreased metabolic capacity
* Decreased kidney function
pregnacy and lactation factor in toxicity
Hormone changes can affect metabolism
Circulatory changes can alter distribution
Increased susceptibility of fetus to some toxicants
Excretion of fat soluble chemicals in milk
* Organochlorines, fat soluble pesticides
* Lead
* Tremetone (White snakeroot toxins)
disease conditions determining toxicity
Heart disease – cardiotoxic plants, feed additives
Kidney disease – decreased excretion
Liver disease
* Decreased metabolic detoxification
* Decreased proteins, e.g., albumin and clotting factors
