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W. TassaneeyakulW. Tassaneeyakul 11
Principles of Principles of Toxicology :Toxicology :
The Study of PoisonsThe Study of Poisons
Wongwiwat TassaneeyakulWongwiwat Tassaneeyakul
Department of ToxicologyDepartment of Toxicology
Khon Kaen UniversityKhon Kaen University
W. TassaneeyakulW. Tassaneeyakul 22
To know scope and definition of toxicology,
Describe how toxicologist
work and manage
toxicants,Understand dose-
response relationship and
interactions
W. TassaneeyakulW. Tassaneeyakul 33
August 21st, 1986, 9:30 pm
>1700 people and 3000 dead cow!!!
W. TassaneeyakulW. Tassaneeyakul 44
Asia's arsenic crisis deepensAnother 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 Thalidomide tragedytragedy
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Fixed drug eruptionFixed drug eruption
Drug rashDrug rash SJSSJS
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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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ตุ�ลาคม 2547 คนงานโรงสี�ขอนแก่�น เสี�ยชี�วิ�ตุขณะลงไปทำ�าควิามสีะอาดทำ�อสี�งข�าวิ
W. TassaneeyakulW. Tassaneeyakul 99
W. TassaneeyakulW. Tassaneeyakul 1010
TOXICOLOGYTOXICOLOGY : The study of the : The study of the adverse effectsadverse effects of a of a toxicanttoxicant on on living organismsliving organisms..
Toxicology related closely to Pharmacology, Biochemistry, Molecular biology, Chemistry, Epidemiology, Pathology, Genetics, Public Health, Medicine, etc.
W. TassaneeyakulW. Tassaneeyakul 1111
HazardHazard – physical situation that can – physical situation that can damage:damage:
– people people – plant plant – EnvironmentEnvironment
RiskRisk – likelihood of hazard occurring – likelihood of hazard occurring
RiskRisk = = hazardhazard * probability * * probability * consequenceconsequence
W. TassaneeyakulW. Tassaneeyakul 1212Source: Muckter, 2003
W. TassaneeyakulW. Tassaneeyakul 1313
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
W. TassaneeyakulW. Tassaneeyakul 1414
COMMON TOXICOLOGY QUESTIONSCOMMON 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)
W. TassaneeyakulW. Tassaneeyakul 1515
Routes of Entry:Routes of Entry:
OralOral == Ingestion by mouthIngestion by mouth
DermalDermal == Skin exposureSkin exposure
InhalationInhalation == Absorbed by lungsAbsorbed by lungs
OcularOcular = = Eye exposureEye exposure
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Why human have to concern with other species toxicology and/or environmental health?
W. TassaneeyakulW. Tassaneeyakul 1717
Classification of Toxic AgentsClassification of Toxic Agents
– Target organ/site Target organ/site (e.g., liver, kidney, blood, (e.g., liver, kidney, blood, lung, nerves)lung, nerves)
– Use Use (e.g., pesticide, solvent, food additive)(e.g., pesticide, solvent, food additive)– Effects Effects (e.g., cancer, mutation, liver injury)(e.g., cancer, mutation, liver injury)– Labeling requirements Labeling requirements (e.g., explosive, (e.g., explosive,
flammable, oxidizer)flammable, oxidizer)– Poisoning potential Poisoning potential (e.g., very or slightly (e.g., very or slightly
toxic)toxic)
W. TassaneeyakulW. Tassaneeyakul 1818
““Allein die Dosis macht, Allein die Dosis macht, daß ein Ding kein Gift daß ein Ding kein Gift
istist.”.”
(“Dose determines toxicity”)
Dose-Response Dose-Response RelationshipRelationship
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All All substancessubstances are poisons; are poisons; there isthere is nonenone that is not a that is not a poison. The rightpoison. The right dose dose differentiates a poison and a differentiates a poison and a remedy.remedy.
Paracelsus Paracelsus
(1493- 1541)(1493- 1541)
THE DOSE MAKES THE THE DOSE MAKES THE POISONPOISON
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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
What is a Response?
W. TassaneeyakulW. Tassaneeyakul 2222
Dose-responseDose-response
EFFECT
linear,no threshold
non-linear,threshold
Dose
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LDLD5050 Comparison Comparison
Chemical LD50 (mg/kg) Ethyl Alcohol 10,000 Sodium Chloride 4,000 Ferrous Sulfate 1,500 Morphine Sulfate 900 Strychnine Sulfate 150 Nicotine 1 Black Widow 0.55 Curare 0.50 Rattle Snake 0.24 Dioxin (TCDD) 0.001 Botulinum toxin 0.0001
W. TassaneeyakulW. Tassaneeyakul 2727
Toxicity rating or class
Probable lethal oral dose for human
Dosage for average adult
1. Practically nontoxic
> 15 g/kg more than 1 quart (>0.94 L)
2. Slightly toxic 5-15 g/kg between pint and quart (0.47-0.94L)
3. Moderately toxic
0.5-5 g/kg between ounce and pint (28 mL-0.47L)
4. Very toxic 50-500 mg/kg between teaspoon and ounce (5-28 mL)
5. Extremely toxic
5-50 mg/kg between 7 drops and teaspoon
6. Supertoxic < 5 mg/kg a taste (less than 7 drops)
W. TassaneeyakulW. Tassaneeyakul 2828
THE DOSE-RESPONSE RELATIONSHIP
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
W. TassaneeyakulW. Tassaneeyakul 2929
W. TassaneeyakulW. Tassaneeyakul 3030
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Acute vs. Chronic
Allergic (hypersensitivity)
Idiosyncratic (e.g. G6PD def.)
Local vs. Systemic
Reversible vs. Irreversible
Type of Toxic Response
W. TassaneeyakulW. Tassaneeyakul 3232
Acute Toxicity:Acute Toxicity:
(short-term exposure)(short-term exposure)
TIME: Minutes or Hours
Threshold Concentration
Blo
od
or
Tis
su
e
C
on
ce
ntr
atio
n
SYMPTOMS
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Chronic Toxicity:Chronic Toxicity:(repeated exposures)(repeated exposures)
x
Threshold concentrat ion
SYMPTOMS
TIME: Weeks, months, years
Blo
od o
r T
issue
Co
ncentr
atio
n
x
x
x
x
x
x
x
W. TassaneeyakulW. Tassaneeyakul 3434
Carcinogens:Carcinogens:– Cause cancerCause cancer
Mutagens:Mutagens:– Cause mutations in an organism’s genetic materialCause mutations in an organism’s genetic material
Teratogens:Teratogens:– cause birth defects in offspring following exposure cause birth defects in offspring following exposure
of a pregnant femaleof a pregnant female
Examples: Chronic Examples: Chronic EffectsEffects
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W. TassaneeyakulW. Tassaneeyakul 3636
Drug rash
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Dose-response relationship: LEADDose-response relationship: LEADdecreased erythrocyte delta-ALAD activityincreased zinc protoporphyrin
anemia
CNS effectsdecreased peripheral nerve conductivityNervous paralysis, lead colics
Adapted from Elinder C-G et al., Biologisk monitoring av metallerhos människa. Arbetsmiljöfonden, Uppsala, 1991
W. TassaneeyakulW. Tassaneeyakul 3838
Additive : Additive : 2+2 2+2 = 4= 4Synergism : Synergism : 2+3 2+3 = 10= 10Potentiation :Potentiation : 0+30+3 = 5= 5Antagonism :Antagonism : 2+(-2)2+(-2) = 0= 0
Chemical antagonismChemical antagonismDispositional antagonismDispositional antagonismFunctional antagonismFunctional antagonismPharmacological antagonismPharmacological antagonism
Toxicity Interactions
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W. TassaneeyakulW. Tassaneeyakul 4040
Synergist / Synergist / SynergismSynergism::
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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W. TassaneeyakulW. Tassaneeyakul 4545Source: “A Primer on Toxics”
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ConclusionConclusion
What is toxicology ?What is toxicology ? Toxicity, poison, hazard, risk ?Toxicity, poison, hazard, risk ? Why dose-response study is so important in Why dose-response study is so important in
toxicology?toxicology? How can we classify type of toxicity ?How can we classify type of toxicity ? Why people response differently to toxicant ? Why people response differently to toxicant ?
W. TassaneeyakulW. Tassaneeyakul 4848
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THE DOSE MAKES THE THE DOSE MAKES THE POISONPOISON