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Principles of Toxicology :
The Study of Poisons
Wongwiwat Tassaneeyakul
Department of Toxicology
Khon Kaen University
[email protected]
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 To know scope and definition
of toxicology,
 Describe how toxicologist
work and manage toxicants,
 Understand dose-response
relationship and interactions
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August 21st, 1986, 9:30 pm
>1700 people and 3000 dead cow!!!
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Asia's arsenic
crisis deepens
Another Indian state
succumbs to well water
poisoning.
15 February 2003
TOM CLARKE
Hand-pump wells tap
into natural
accumulations of
arsenic.
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Thalidomide tragedy
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Fixed drug eruption
Drug rash
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SJS
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A villager uses a dip
net to remove dead
fish from the Bang
Pakong river. The
fish, bred in floating
baskets, died from
pollution in the river.
_ TAWATCHAI KEMGUMNERD
Friday 15 November
2002 BangkokPost
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ตุลาคม 2547
ี อนแก่น
คนงานโรงสข
ี ชวี ต
เสย
ิ ขณะลงไปทา
่ ข้าว
ความสะอาดท่อสง
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TOXICOLOGY : The study of the
adverse effects of a toxicant on
living organisms.
Toxicology related closely to
Pharmacology, Biochemistry, Molecular
biology, Chemistry, Epidemiology, Pathology,
Genetics, Public Health, Medicine, etc.
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Hazard – physical situation that can
damage:
– people
– plant
– Environment
Risk – likelihood of hazard occurring
Risk = hazard * probability * consequence
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Source: Muckter, 2003
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1. Toxicant/ Toxin/ Poison/ Hazard
 any agent capable of producing a deleterious
response in a biological system
2. Adverse/Toxic effects
 any unwanted change from an organism’s normal
state
 dependent upon the concentration of active
compound at the target site (receptor)for a
sufficient time.
3. Living organism
 cellular target sites/ storage depots and enzymes
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COMMON TOXICOLOGY QUESTIONS
1. What is a poison?
2. Where dose it come from? (exposure Q)
3. How does it get into living organism?
(exposure Q)
4. What does it do to living organism?
(mechanism Q)
5. How can we treat/prevent this toxicity?
(clinical Q)
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Routes of Entry:
Oral
=
Ingestion by mouth
Dermal
=
Skin exposure
Inhalation
=
Absorbed by lungs
Ocular
=
Eye exposure
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Why human have to
concern with other
species toxicology
and/or
environmental
health?
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Classification of Toxic Agents
–
–
–
–
–
Target organ/site (e.g., liver, kidney, blood,
lung, nerves)
Use (e.g., pesticide, solvent, food additive)
Effects (e.g., cancer, mutation, liver injury)
Labeling requirements (e.g., explosive,
flammable, oxidizer)
Poisoning potential (e.g., very or slightly
toxic)
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Dose-Response
Relationship
“Allein die Dosis macht,
daß ein Ding kein Gift ist.”
(“Dose determines toxicity”)
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THE DOSE MAKES THE POISON
All substances are poisons;
there is none that is not a
poison. The right dose
differentiates a poison and a
remedy.
Paracelsus
(1493- 1541)
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What is a Response?
Change from normal state
could be on the molecular, cellular,
organ, or organism level--the symptoms
Graded vs. Quantal
degrees of the same damage vs. all or
none
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Dose-response
EFFECT
non-linear,
threshold
linear,
no threshold
Dose
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LD50 Comparison
Chemical
Ethyl Alcohol
Sodium Chloride
Ferrous Sulfate
Morphine Sulfate
Strychnine Sulfate
Nicotine
Black Widow
Curare
Rattle Snake
Dioxin (TCDD)
Botulinum toxin
LD50 (mg/kg)
10,000
4,000
1,500
900
150
1
0.55
0.50
0.24
0.001
0.0001
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Toxicity rating
or class
1. Practically
nontoxic
2. Slightly toxic
3. Moderately
toxic
Probable lethal
oral dose for
human
> 15 g/kg
5-15 g/kg
0.5-5 g/kg
4. Very toxic
50-500 mg/kg
5. Extremely
toxic
5-50 mg/kg
6. Supertoxic
< 5 mg/kg
Dosage for average
adult
more than 1 quart (>0.94 L)
between pint and quart (0.470.94L)
between ounce and pint (28
mL-0.47L)
between teaspoon and ounce
(5-28 mL)
between 7 drops and teaspoon
a taste (less than 7 drops)
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THE DOSE-RESPONSE RELATIONSHIP
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed.,
New York: McGraw-Hill, 1996).
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Type of Toxic Response
Acute vs. Chronic
Allergic (hypersensitivity)
Idiosyncratic (e.g. G6PD def.)
Local vs. Systemic
Reversible vs. Irreversible
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Acute Toxicity:
(short-term exposure)
Blood or Tissue
Conc ent rat ion
Threshold Concentration
SYMPTOMS
TIME: Minut es or Hours
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Chronic Toxicity:
(repeated exposures)
Threshold concent rat ion
Blood or Tissue
Conc entration
SYMPTOMS
x
x
x
x
x
x
x
x
TIME: Weeks, mont hs, years
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Examples: Chronic Effects
 Carcinogens:
– Cause cancer
 Mutagens:
– Cause mutations in an organism’s genetic material
 Teratogens:
– cause birth defects in offspring following exposure
of a pregnant female
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Drug rash
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Dose-response relationship: LEAD
decreased erythrocyte delta-ALAD
activity
increased zinc protoporphyrin
anemia
CNS effects
decreased peripheral nerve
conductivity
Nervous paralysis, lead colics
Adapted from Elinder C-G et al., Biologisk monitoring av metaller
hos människa. Arbetsmiljöfonden, Uppsala, 1991
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Toxicity Interactions
Additive :
Synergism :
Potentiation :
Antagonism :
2+2 = 4
2+3 = 10
0+3
=5
2+(-2)
=0
Chemical antagonism
Dispositional antagonism
Functional antagonism
Pharmacological antagonism
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Synergist / Synergism:
Synergism is increased activity (toxicity)
resulting from the effect of one chemical on
another.
LD50 DDT
=
250 mg/kg
LD50 synergist
=
1,000 mg/kg
LD50 DDT + synergist
=
50 mg/kg
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Source: van den Brandt et al. 2002
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Source: “A Primer on Toxics”
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Conclusion
 What is toxicology ?
 Toxicity, poison, hazard, risk ?
 Why dose-response study is so important in
toxicology?
 How can we classify type of toxicity ?
 Why people response differently to toxicant ?
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THE DOSE MAKES THE POISON
สรรพสงิ่ ทว่ ั ถ้วนล้วนมีพษ
ิ
พึงพินจ
ิ ตรองไตร่ให้ถว้ นถี่
คุณประโยชน์อก
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ต่างก ันทีข
่ นาดใชใ้ ห้สงวรณ์
วงศว์ วิ ัฒน์ ทัศนียกุล
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