Principles of Toxicology

Poisonous Plants Class

Spring Semester 2010

Terminology

• Toxicology - the study of adverse effects of xenobiotics on living organisms.

• Xenobiotic - a chemical compound that is foreign to a living organism

• Poison – any agent capable of producing a deleterious response in a biological system.

• LD50 – median lethal dose, or the dose required to kill 50% of treated animals

• Half Life (T1/2) – time required for one half of a substance to be removed

Key Principles

• Risk - possibility of loss or injury

– Risk = Hazard X Exposure

– Hazard – intrinsic toxic properties

• Individual Sensitivity

– Not all are created equal

• Resistant and Susceptible

Dose

• Dose - the measured quantity of a

therapeutic agent to be taken at one time

• mg of agent / kg body weight

– (mg/kg)

“All substances are poisons;

there is none which is not a poison.

The right dose differentiates a poison from

a remedy.”

Paracelsus (1493-1541)

The Dose Makes the Poison

Water 42,860

Sucrose 14,000

Ethyl alcohol 10,000

Salt (sodium chloride) 4,000

Iron (Ferrous sulfate) 1,500

Morphine 900

Mothballs 500

Acetaminophen (Tylenol) 350

Aspirin 250

DDT 250

Cyanide 10

Strychnine sulfate 2

Nicotine 1

Tetrodotoxin (from fish) 0.1

Abrin (plant lectin) < 0.0001

Botulinum Toxin 0.00001

Agent LD50 (mg/kg)

The Dose Makes the Poison

“Poisons and medicines are oftentimes the

same substance given with different

intents.”

Peter Mere Latham (1789-1875)

The Dose Makes the Poison

• Poisonous plants and nutritious feeds are

oftentimes the same substance consumed

at different amounts.

– For example:

• Alfalfa

• Lupine

• Larkspur

• Etc

Effects of Amount on Response

Effects of Size on Response

Dose-Response Relationship

Dose

0 1 2 3 4 5 6 7 8 9 10

Re

sp

on

se

(%

)

0

10

20

30

40

50

60

70

80

90

100

110

Toxicity

The Timing Makes the Poison

• Teratogen - of, relating to, or causing

developmental malformations

– i.e., something that will produce birth defects

Crooked Calf

Example of Lupine-induced

“crooked calf disease”

Malformed Lamb

Fate of Plant Poisons in Livestock

• Risk = Hazard X Exposure

• Toxicokinetics – what happens to a xenobiotic once it enters a body; in terms of its absorption, distribution, metabolism, and excretion

• ADME

– Absorption

– Distribution

– Metabolism

– Elimination/Excretion

Exposure & Absorption

Route of exposure

1) Skin (dermal)

2) Lung (inhalation)

3) Oral (gut)

Frequency of Exposure

• Number of Exposures

– 1 beer

– 4 beers

• Time between Exposures

– 4 Beers in an hour

– 4 Beers in 4 Days

Single vs. Multiple Doses

Time (h)

0.0 0.5 1.0 1.5 2.0 2.5

Seru

m P

ois

on C

oncentr

ation

(mg o

f P

ois

on / m

l of seru

m)

0

2

4

6

8

10

# of Doses

-1 0 1 2 3 4 5

0

5

10

15

20

25

Seru

m P

ois

on C

oncentr

ation

(mg o

f P

ois

on / m

l of seru

m)

1 2 3 4

•Acute Exposure

•Sub-acute Exposure

•Sub-chronic Exposure

•Chronic Exposure

Duration of Exposure

Distribution

• Where the compound goes and where it

accumulates

– (body water, fat, bone, muscle)

• Water soluble (hydrophilic) vs. fat soluble

(hydrophobic)

Metabolism

• How the body breaks down a xenobiotic• What it turns into• How fast it does it

OO OCH3

O

OH

OH

O

O

Metabolism

OO OCH3

O

OH

OH

O

OO OCH3

O

OH

OH

O

HO

HS

OO OCH3

O

OH

OH

O

HO

HN

NN

N

O

H2N

Aflatoxin B1 Aflatoxin B1-8,9-epoxide

Aflatoxin B1-glutathione adductAflatoxin B1-N7-guanine adduct

Elimination/Excretion

• Removal of xenobiotic from body

– Urinary

– Fecal

• Non-absorbed material

• Biliary excretion

– Exhalation

– Milk

– Sweat and Saliva

Slow vs. Rapid Elimination

# of Doses

-1 0 1 2 3 4 5

0

5

10

15

20

25

Se

rum

Po

iso

n C

on

ce

ntr

atio

n

(mg

of P

ois

on

/ m

l of se

rum

)

1 2 3 4

# of DosesTime

0 1 2 3 4

To

xin

Co

nce

ntr

atio

n

0

5

10

15

20

“The sensitivity of the individual

differentiates a poison from a remedy. The

fundamental principle of toxicology is the

individual’s response to a dose.”

Steven G. Gilbert (1997)

Individual Variation

Dose-Response RelationshipDose-Response Relationship

Dose (mg/kg)

0 1 2 3 4 5 6 7 8 9

Response F

requency (

%)

0

5

10

15

20

25

30

Susceptibility & Variability

• Differences in ADME

• Young or Old

• Male or Female

• Environmental Differences

• Genetic Differences

• Species Differences

Risk Assessment

Process of estimating association

between an exposure and the incidence

of some adverse outcome

-Determine risk of livestock grazing in a given

area