Lecture 2- basic principles of toxicology

basic principle #1

the dose makes the poison

NOAEL

no observed adverse effect level

LD50

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

MTD

minimum toxic dose

MLD or MLC

minimum lethal dose concentration

what toxicity parameters is the most clinical used

minimum toxic dose

T/F exposure does not equal intoxication

true

what must happen for a toxic effect (toxicokinetics) to occur

the toxin must be absorbed and reach its site of action at a high enough concentration and for a sufficient period of time to cause a toxic effect

what is basic principle 2

basic toxicokinetics

what are the basic events of basic toxicokinetics

ADME

absorption

distribution

metabolism

excretion

what is absorption

how does it get into the body

can we minimize absorption

distribution

where dos it go

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

metabolism

what happens to it when it gets there?

big species differences can exist for various metabolic pathways

can we block a metabolic pathway/ enzyme and prevent or limit production of a more toxic metabolite

excretion

how does it get out of body?

primary routes of excretion

urinary

biliary/ fecal

lesser: milk, sweat, saliva

acute

generally 24 hours or less

usually involves exposure over less than a day

subacute

>24 hours but < 1 month

a subacute toxicity study is usually 14-28 days of exposure

subchronic

several months definitely less than a year

a subchronic toxicity study is often 3 months of exposure

chronic

over a significant portion of the lifetime

a chronic toxicity study is often 2 years of exposure

basic principle 3

the typical dose response curve has imporant exceptions/ variations

hormesis

small exposures are protective, large are dangerous

therapeutic index

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

many factors influence toxicity include

• Characteristics of the animal/animals exposed

• Route of exposure

• Frequency of exposure

• Characteristics of the toxicant

• Environmental conditions

characteristics of the animal

• SPECIES

• Genetic differences (polymorphisms)

• Age

• Sex, reproductive status

• Concurrent disease (comorbidities)

• Concurrent exposure to other drugs or chemicals

• Nutritional status

basic principle 4

many factors influence toxicity

characteristics of the toxicant

• Formulation, vehicle

• Valence state of metals

• Ionization

• Decomposition

• Impurities

• Strain/subspecies

frequency of exposure

• One time exposure

• Repeated exposures

• Cumulative effects

environmental conditions

• Drought

• Time of year

• Growth stage

• Temperature

• Photo period

• Winds

what should you ask instead of is this toxic

at what dosage

in what species

under what condition

why calculate dose of exposure

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

why not just treat any exposure

Risks (and expense) of treatment may outweigh risk of intoxication

aggressiveness of treatment is determined by

severity of intoication

What kind of rat bait? (Active ingredient!)

How much did he eat?

Is that enough to cause poisoning?

Enough to cause death?

GET THE LABEL!!!

owner thinks they used one or two of the bait blocks

there are 6 blocks in the package now

you must assume the pet ate all 4 of the unaccounted for packages

calculate MLD, MTD, and potentially ingested

why calculate dose of exposure

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

why not just treat any exposure

Risks/expense of treatment may outweigh risk of intoxication

Aggressiveness of treatment will be determined by severity of potential intoxication