Exam 1 Objectives: Intro, Toxicokinetics, and Household Toxins

Question 1

Introduction to Clinical Toxicology objectives

Be able to estimate the NOEL and NOAEL from dose-response data

Answer 1

NOEL is defined as the highest dose at which a significant effect
could NOT be detected. Similarly, a NOAEL is the highest dose where a
significant adverse effect could NOT be found.

Question 2

Introduction to Clinical Toxicology objectives

Be able to estimate the LOEL and LOAEL from dose-response data

Answer 2

The LOEL is defined as the lowest dose at which a significant
effect COULD be found. The LOAEL is the lowest dose where a
significant adverse effect COULD be found.

Question 3

Introduction to Clinical Toxicology objectives

Be able to estimate the Therapeutic Index (TI) and Standard Safety Margin (SSM) of a toxicant based on dose-response data for efficacy and toxicity

Answer 3

TI=LD50/ED50, SSM=LD1/ED99

Question 4

Introduction to Clinical Toxicology objectives

Be able to explain the difference between an acute vs. chronic toxicant exposure

four total

Answer 4

Acute – Exposure to single or multiple doses over a 24 hour period
Subacute – Exposure to multiple doses of a toxicant for greater than 24 hours
but for as long as 30 days.
Subchronic – Exposure lasting from 1-3 months.
Chronic – Exposure for 3 months or longer.

Question 5

Introduction to Clinical Toxicology objectives

Be able to carry out relatively rudimentary estimations and conversions to determine if exposure of a toxicant in a specific formulation reaches a toxic level. This is basically a review of the examples done in this lecture with the Blue Buffalo dog food and the rodenticide bait. Any problem that I will potentially give on an exam will not be as complex as these examples but may involve a simple conversion or two to reach a conclusion.

Answer 5

Example given in lecture: If the toxicity of a cholecalciferol rodenticide is 2 mg/kg of body weight and the bait concentration is 0.075%, is a 2-ounce package of bait likely to be toxic to a 35 lb. dog that consumes the entire package at one time?
a. If in ounces, make sure to convert the amount ingested to grams (1oz=28.35g)
b. put percent concentration over 100g.
c. Make sure the weight of the dog is in kg (1lb=0.45kg)
d. Multiply the amount ingested by g (a) by concentration (b)
e. Divide the amount ingested (d) by the weight of the dog (c ), if g/kg, multiply by 1000mg to get mg.

Question 6

toxicokinetics objectves

What factors affect the passage of toxicants across biological membranes?

Answer 6

1. Concentration Gradient Across the Membrane
2. Surface Area of the Membrane
3. Toxicant Permeability
4. Macromolecule Binding

Question 7

toxicokinetics objectves

What physiologic factors differentiate the stomach vs. the small intestine in terms of the ability to absorb toxicants?

Answer 7

The surface area, the Structure of the stomach is set up for secretion and movement. The small intestine and the rest of the GI are designed for absorbing nutrients and thus have a much larger area on the luminal surface.

Question 8

toxicokinetics objectves

What role does the liver play in the oral bioavailability of toxicants?

Answer 8

Xenobiotics absorbed in the GI proceed via the portal vein to the liver.

Question 9

toxicokinetics objectives

What factors play a role in the dermal absorption of toxicants? Would a water-soluble toxicant be expected to cross through the skin?

what are the factors in absorption?

Answer 9

Compound Characteristics: Lipophilic to cross stratum corneum, Hydrophilic enough to go into the more aqueous dermal layer
Physiologic & Other Factors: Surface Area, Perfusion
Absorption=surface area x permeability x perfusion

Question 9

toxicokinetics objectves

What is the difference between diffusion- and perfusion-limited drug distributions?

Answer 9

Perfusion limited: drug distribution to tissues is equal to the amount of blood flow that each tissue receives

Diffusion limited: The major physiochemical properties of a drug that dictate ease of entry into a tissue are: lipid to water partitioning and degree of ionization

Question 10

toxicokinetics objectves

What role can metabolism play in species differences in the toxicity of a toxicant?

Answer 10

Species variability can be both in the rate of metabolism as well as what metabolites are formed. Variability exists across sexes, breeds, and within breeds for dogs. This variability is due to genetics, environment, physiologic variability, and multiple other factors.

Question 11

toxicokinetics objectves

Does metabolism always involve the disappearance of a toxicant? What other role can metabolism play in toxicant exposure?

Answer 11

metabolites can be active, toxic, inactive, non toxic. metabolizing can also cause toxicants to take effect.

Question 12

toxicokinetics objectves

How are toxicants eliminated from the body? What role does the liver play? What role does the kidney play?

what are the factors of each?

Answer 12

Urine, Hair/fur, Feces, Skin, Sweat, Milk, Saliva, Whiskers, Exhalation

Liver: The primary role of the liver is biotransformation reactions and transfer of compounds into the bile via active transport
Factors are: Blood Flow, Enzymatic Activity, Protein Binding.
High liver extraction is dependent on blood flow, and low extraction: protein binding can play a role.

Kidney: Factors are: Filtration – Glomerulus, Active Secretion – Proximal Tubule, Reabsorption - Nephron
The kidney is freely permeable to compounds up to 7000 MW

Question 13

toxicokinetics objectves

What are the three factors involved in renal elimination and what factors influence how dominant a role they play in renal elimination?

Answer 13

also think on urinary ph and reabsorption
In the question above but: Factors are: Filtration – Glomerulus, Active Secretion – Proximal Tubule, Reabsorption - Nephron

Question 14

toxicokinetics objectves

Be able to estimate the bioavailability of a toxicant given appropriate AUC data from various routes and doses of administration.

Answer 14

Bioavailability = AUCRouteX·DoseIV/
AUCIV·DoseRouteX

Question 15

toxicokinetics objectves

Be able to describe how the terminal half-life of a toxicant can influence the treatment of a poisoned animal.

Answer 15

The terminal half-life is an indicator of how long a xenobiotic will persist at a concentration presenting a biological effect. This may be an important indicator of treatment duration or residue time.

Question 16

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

Xylitol

Answer 16

Endocrine/metabolic: The canine pancreas reacts to xylitol by releasing insulin leading to hypoglycemia

Gastrointestinal: Vomiting, diarrhea, melena

Hepatobiliary: Acute hepatic necrosis, elevated liver enzymes, icterus, coagulopathy, hypoglycemia, hepatic encephalopathy

Nervous: Behavioral changes, weakness, ataxia, tremors, seizures

Question 17

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

Methylxanthines

Answer 17

Gastrointestinal: Nausea, vomiting, diarrhea

Cardiovascular: Tachycardia, hypertension, VPCs, tachyarrhythmias, bradycardia (rare)

Nervous: Hyperexcitability, ataxia, seizures

Musculoskeletal: Muscle tremors

Renal/urological: PU/PD, urinary incontinence

Respiratory: Tachypnea, respiratory failure (high dose)

Endocrine/metabolic: hypokalemia

Question 18

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

(Cleaning Products) Acids

Answer 18

Acids:
Cause rapid surface protein coagulation, leading to coagulation necrosis followed by the formation of a thick eschar
Significant tissue damage from corrosive injury may result in stricture formation
Organs having direct contact with the acid are those most at risk
Gastrointestinal – mild tissue irritation to significant ulceration (Oral Cavity, Esophagus, Stomach, Doudenum)
Skin – mild irritation to severe corrosive injury of the superficial layers of the skin followed by eschar formation

Other notes:
Exposure can be oral, topical, ocular or respiratory

Animal exposures are usually due to ingestion or dermal contact. Small ingestions/tastes of corrosive acids are unlikely to result in severe tissue damage. Strong acids have a sour taste, usually cause immediate pain upon tissue contact and thus large ingestions are rare.

Weak (pH 2-4) or dilute acids may cause mild irritation
Strong acids (pH<2) or concentrated acids can cause corrosive injury

Question 19

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

(Cleaning Products) Alkalis

Answer 19

Alkalines:
Cause ** liquefication necrosis** with resulting edema and inflammation and rapidly penetrate deep into tissues, often involving multiple layers (transmural necrosis)
Triglycerides in cell membranes become saponified by hydroxyl ions, resulting in membrane lysis. Proteins become denatured, resulting in function loss and cell death
Thrombosis occurs in arterioles and venules
Significant tissue damage from corrosive injury may result in stricture formation

other notes:
Animal exposures are usually due to ingestion or dermal contact

Small ingestions/tastes of alkaline corrosives are unlikely to result in severe tissue damage. Alkaline products typically have no odor or taste; thus, larger ingestions may occur. Bittering agents may be added to deter ingestion.

Weak (pH 10-11) or dilute alkalis may cause mild irritation
Strong alkalis (pH>11-12) or concentrated alkalis can cause corrosive injury

Question 20

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

Essential Oils/Liquid Potpourri

Answer 20

Pennyroyal Oil – hepatobiliary
Clove Oil – hepatobiliary
Citrus Oil/d-limonene – GI, musculoskeletal, nervous
Peppermint Oil – GI, nervous
Cinnamon Oil – GI
Oil of Wintergreen – GI, hemic, hepatobiliary, respiratory

Toxicity data specific for cats and dogs are limited
Liquid potpourri also contains cationic surfactants which can cause some of the clinical signs. Small ingestion (2-3 licks) and dermal exposures may result in corrosive injury

Question 21

Household and Industrial Toxins objectives

What specific treatments exist for each of the household/industrial toxins that were discussed?

for xylitol

Answer 21

Early decontamination, supportive care for hypoglycemia and hepatic injury, and monitoring, Emesis induction for asymptomatic patient (1-2 hours post ingestion), Blood glucose monitoring and dextrose treatment, Liver protectant/supportive medications: SAMe, silymarin, NAC

Question 22

Household and Industrial Toxins objectives

What specific treatments exist for each of the household/industrial toxins that were discussed?

for Methylxanthines

Answer 22

Decontamination:
Induce emesis for caffeine within 1-2 hours if asymptomatic.
Chocolate emesis within 6 hours of ingestion, especially with large ingestions or if the patient appears visibly bloated.
Gastric lavage with large volume ingestion in symptomatic patients following stabilization.
Activated charcoal once with a cathartic and then repeated without.
Urinary catheterization or frequent urination to decrease potential reabsorption of methylxanthines.

Supportive Care:
IV fluid therapy – hydration, perfusion and enhance urinary elimination
Sedation- acepromazine, butorphanol
Seizures – diazepam, midazolam
Sinus tachyarrhythmias and hypertension – beta blockers
Ventricular arrhythmias - lidocaine

Question 23

Household and Industrial Toxins objectives

What specific treatments exist for each of the household/industrial toxins that were discussed?

for Acids and alkalis

Answer 23

Diagnostics:
Endoscopy – examine the esophagus, stomach and duodenum
CBC or PCV/TS- blood loss anemia, WBC change with GI perforation and sepsis

Therapeutics:
Decontamination of the skin or oral membranes with large volumes of water or saline (start at home if possible). Wash eyes with tap water
GI decontamination is contraindicated
IV as opposed to PO drugs if possible
Gastroprotection- sucralfate, H2 blockers, PPIs
Fluid therapy
Analgesia

Question 24

Household and Industrial Toxins objectives

What specific treatments exist for each of the household/industrial toxins that were discussed?

essential oil/ liquid potpourri

Answer 24

Decontamination:
Dermal – wash with hand/dishwashing detergent
Ocular – irrigate eyes with copious amounts of water
Oral – Non-caustic: induction of emesis in asymptomatic patients followed by activated charcoal
Caustic: dilution with milk or water

Symptomatic and Supportive Care:
Caustic- treat similar to acids/alkalis
Antiemetics
Hepatoprotectants (silymarin, NAC, SAMe)

Question 25

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

batteries (lithium disk and dry cell)

Answer 25

**Lithium Disk batteries **contain no corrosive compounds.. But.. The esophagus becomes increasingly alkaline on the cathode side and acidic on the anode side as current passes through the battery resulting in tissue damage/possible perforation

Dry cell batteries (alkaline dry cells are the majority of household batteries) contain potassium hydroxide or sodium hydroxide. When the compounds come in contact with tissue due to rupture of the casing, tissue damage can occur.

Question 26

Household and Industrial Toxins objectives

What specific treatments exist for each of the household/industrial toxins that were discussed?

batteries

Answer 26

• Radiograph to identify retained battery
• Small amounts of water to dilute until evaluation complete
• Endoscopic or surgical removal of battery
• GI protectants and antacids to allow for ulceration to heal
• Antimicrobials if necessary
• Analgesics if necessary
• In children, most serious outcomes and greatest number of deaths with large diameter lithium batteries (>20 mm) due to exsanguination after fistulization into major vessels (following esophageal entrapment)
• Outcomes are dependent on length of exposure and amount of damage: Long-term esophageal malformation, Esophageal strictures

Question 27

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

fertilizers

Answer 27

Some fertilizers contain Milorganite, a sewage-based fertilizer, that has potential for GI signs, muscle pain and stiffness

Cacao bean mulch made from cocoa shells can have theobromine concentrations of 56-900 mg/oz and thus can cause methylxanthine toxicity

Question 28

Household and Industrial Toxins objectives

What is the mechanism of action for the household/industrial toxins that were discussed?

Ethylene Glycol (EG)/Diethylene Glycol (DEG)

Answer 28

Metabolism results in **oxalic acid **that binds calcium to form calcium oxalate crystals that deposit in the kidneys. Metabolic products also cause metabolic acidosis. For DEG, diglycolic acid also causes kidney dysfunction but does not form insoluble crystals. Toxicity may be related to calcium chelation however.

Question 29

Household and Industrial Toxins objectives

What specific treatments exist for each of the household/industrial toxins that were discussed?

Ethylene Glycol (EG)/Diethylene Glycol (DEG)

Answer 29

Inhibit metabolism – fomepizole or ethanol to compete with EG/DEG for alcohol dehydrogenase. Both work fine but ethanol requires more intensive care (hospitalization)
Correct acid-base and electrolyte derangements- calcium gluconate for severe hypocalcemia, bicarbonate for pH<7.0
Correct fluid imbalances – isotonic fluids for vomiting, diarrhea, polyuria
Remove parent compound and metabolites – hemodialysis and extracorporeal blood purification if available
Supportive care for acute kidney injury – antiemetics, gastrointestinal protectants, and phosphate binders

Question 30

Household and Industrial Toxins objectives

What are the sequelae associated with the toxicosis of respective agents and how do they coordinate with treatment options?

Ethylene Glycol (EG)/Diethylene Glycol (DEG)

Answer 30

for DEG, unknown.
Clinical Presentation
Acute Signs – 0.5-12 hours
Gastric irritation – nausea vomiting
Plasma hyperosmolality – mental dullness, ataxia

Delayed Signs (12-24 hrs cat, 36-72 hrs dog)
Acute oliguric renal failure- listlessness, depression, anorexia

PK
Ethylene Glycol:
Rapidly absorbed from the GI
Plasma half-life is 3 hours
Some excreted in the urine unchanged
Majority is metabolized by alcohol dehydrogenase with subsequent metabolism leading to oxalic acid

Diethylene Glycol:
Rapidly absorbed from the GI
Rapidly metabolized by alcohol dehydrogenase with subsequent metabolism leading to diglycolic acid
Completely excreted in 36 hours