w. tassaneeyakul 1 principles of toxicology : the study of poisons wongwiwat tassaneeyakul...

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

[email protected][email protected]


To know scope and definition of toxicology,

Describe how toxicologist

work and manage

toxicants,Understand dose-

response relationship and

interactions


August 21st, 1986, 9:30 pm

>1700 people and 3000 dead cow!!!


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.

http://www.nature.com/nsu/profiles/aboutus.html#Clarke

http://www.nature.com/nsu/profiles/aboutus.html#Clarke


Thalidomide Thalidomide tragedytragedy


Fixed drug eruptionFixed drug eruption

Drug rashDrug rash SJSSJS


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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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.


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


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


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)


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


Why human have to concern with other species toxicology and/or environmental health?


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)


““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


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


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?


Dose-responseDose-response

EFFECT

linear,no threshold

non-linear,threshold

Dose


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


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)


THE DOSE-RESPONSE RELATIONSHIP

The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).


Acute vs. Chronic

Allergic (hypersensitivity)

Idiosyncratic (e.g. G6PD def.)

Local vs. Systemic

Reversible vs. Irreversible

Type of Toxic Response


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


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


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


Drug rash


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


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


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


Source: van den Brandt et al. 2002

W. TassaneeyakulW. Tassaneeyakul 4545Source: “A Primer on Toxics”


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 ?


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THE DOSE MAKES THE THE DOSE MAKES THE POISONPOISON

w. tassaneeyakul 1 principles of toxicology : the study of poisons wongwiwat tassaneeyakul...

Documents

definition of toxicology

principles of toxicology

right dose

living organisms

deleterious response

dead fish

organism level

exposure qhow