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