2. Basic Principles of Toxicology

Who was the grandfather of toxicology?

Paracelsus

What is basic principle #1?

everything is toxic at the right dose

What does NOAEL stand for?

no observed adverse effect level

used a lot for drug development and the maximum dose that can be safely used

NOAEL

What does LD50 or LC50 stand for?

lethal dose/concentration that kills 50% of a test population

What does MTD stand for?

minimum toxic dose

lowest level where you will start to see toxic signs

MTD

What does MLD/MLC stand for?

minimum lethal dose/concentration

Which value is likely of most clinical use?

minimum toxic dose (MTD)

True or false: There are species specific values for toxicity. Cats are not small dogs. They have different metabolic profiles. Therefore, toxic things to cats might not be toxic to dogs and vice versa.

true

True or false: Experimental conditions to determine toxicity measures can vary greatly from real-world cases.

true

What is basic principle #2?

exposure does not equal intoxication

How is a toxic effect achieved?

toxin must be absorbed and reach its site of action at a high enough concentration and for a sufficient period of time

What does treatment often involve? Why?

decontamination; get toxin away from animal before it can get absorbed

When it comes to basic toxicokinetics, what is there a big difference between?

species

What are the basic events when it comes to basic toxicokinetics?

A
D
M
E

• absorption

• distribution

• metabolism

• excretion

What are the different routes of absorption?

O
D
I
I

• orally/ingestion

• dermal exposure

• injection

• inhalation

Can we minimize absorption?

yes through decontamination

What are factors when it comes to distribution?

F
P
P
M

• fat solubility vs. water solubility

• protein binding

• pH of tissues and compartments

• many other factors

Can we take advantage of these properties of distribution to limit exposure of the target organ?

depending on the characteristics, can manipulate and trap a drug in a compartment and interfere with the absorption

What happens during metabolism? Why is this important?

biotransformation; metabolites are more readily excreted

What occurs during biotransformation? Where does this commonly occur?

often converted to a more water-soluble product; often in the liver, but also in many other organs

True or false: Big species differences can exist for various metabolic pathways.

true

True or false: Sometimes metabolites are less toxic and sometimes metabolites are more toxic.

true

What are the primary routes of excretion?

1. U

2. B

3. M

1. urinary

2. biliary/fecal

3. milk, sweat, saliva

What is basic principle #3?

the typical dose-response curve has important exceptions/variations

What are some exceptions to the typical dose-response curve?

E
T

• essential nutrients

• therapeutic medications

What vitamins are less likely to cause toxicity? Why?

water soluble vitamins; excreted in urine

ratio of the dose of the drug that produces an unwanted (toxic) effect to that producing a wanted (therapeutic) effect

therapeutic index

What is the formula for the therapeutic index?

LD50 / ED50

What is the safety ratio?

LD1 / ED99

Drugs with what type of therapeutic index should be avoided if possible? Why?

those with a small therapeutic index; want high margins (if 2 tablets were given instead of 1, there is likely chance to cause toxic effects

What type of therapeutic index is this?

small

What type of therapeutic index is this?

large

What is basic principle #4?

many factors influence toxicity

What are some factors that influence toxicity?

C
R
F
C
E

• characteristics of the animal/animals exposed

• route of exposure

• frequency of exposure

• characteristics of the toxicant

• environmental conditions

What are characteristics of the animal that can influence toxicity? Which is the most important?

S
G
A
S
C
C
N

• species

• genetic differences

• age

• sex, reproductive status

• concurrent disease

• concurrent exposure to other drugs or chemicals

• nutritional status

species

What are characteristics of the toxicant that can influence toxicity?

F
V
I
D
I
S

• formulation, vehicle

• valence state of metals

• ionization

• decomposition

• impurities

• strain/subspecies

What are the different types of frequencies of exposure? Why are these important?

O
R
C

• one time exposure

• repeated exposures

• cumulative effects

some toxins may require accumulation from chronic/repeated exposures

What environmental conditions can influence toxicity?

D
T
G
T
P
W

• drought

• time of the year

• growth stage

• temperature

• photo period

• winds

True or false: Asking the question “is this toxic” is the wrong question. Instead, you should ask at what dosage, in what species, and under what conditions.

true

The ________ makes the toxin. Everything is toxic at a ________ enough dose.

dose; high

When are dose calculation used in toxicology?

used in cases involving a known exposure to a specific toxicant

Why is it important to calculate a dose of exposure?

to determine if the dose is high enough to pose a risk of intoxication or death

Why should you not just treat any exposure?

R
A

• risks and expense of treatment may outweigh the risk of intoxication

• aggressiveness of treatment will be determined by the severity of intoxication

KNOW HOW TO DO CALCULATIONS!!!!!