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Principles of Toxicology

This document discusses the key principles of toxicology, including: 1) The different areas of toxicology including mechanistic, descriptive, and regulatory toxicology and their focuses. 2) The spectrum of toxic doses ranging from lethal doses to doses that produce no effects, characterized by the LD50 measurement. 3) Factors that influence toxicity including the route and site of exposure, duration and frequency of exposure, and interactions between chemicals that can have additive, synergistic, or antagonistic effects.

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Reo Vebria NINgsih
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265 views

Principles of Toxicology

This document discusses the key principles of toxicology, including: 1) The different areas of toxicology including mechanistic, descriptive, and regulatory toxicology and their focuses. 2) The spectrum of toxic doses ranging from lethal doses to doses that produce no effects, characterized by the LD50 measurement. 3) Factors that influence toxicity including the route and site of exposure, duration and frequency of exposure, and interactions between chemicals that can have additive, synergistic, or antagonistic effects.

Uploaded by

Reo Vebria NINgsih
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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Principles of toxicology

Indri Garnasih
from:
Chapter 2: David L. Eaton and Curtis D. Klaassen

in Cassaret & Douls


TOXICOLOGY
The Basic Science of Poisons
Curtis D. Klaassen
International Edition

INTRODUCTION TO TOXICOLOGY
Different Area of Toxicology

Spectrum of Toxic Dose

Different Area of Toxicologist


Activities of toxicologists:
Mechanistic
Descriptive

Regulatory

Mechanistic toxicologists
Is concerned with identifying and understanding the cellular,

biochemical and molecular mechanisms by which chemical


exert toxic effects on living organisms
also useful in the design and production of safer alternative

chemicals and in rational therapy for chemical poisoning and


treatment of disease

Descriptive toxicologist
is concerned directly with toxicity testing, provide information for

safety evaluation and regulatory requirements


Toxicity tests in experimental animals are designed to yield

information that can be used to evaluate risks posed to human and


environmental = drugs and food additives
In the chemical industry, not only potential to human, but potential to

birds, fish and balance to the ecosystem

Regulatory Toxicologists
Has the responsibility for deciding, on the basis of data provided

by descriptive and mechanistic toxicologists


Example:
FDA (Food and Drug Administration) : allowing drugs, cosmetics,

and food additives to be sold in the market


Environmental Protection Agency: for regulating most other

chemicals: insecticide, rodenticide, safe drinking water, etc

Spectrum of Toxic Dose


Poison as any agent capable of producing a deletirious

response in a biological system, seriously injuring function or


producing death
Among chemicals there is a wide spectrum of doses needed
to produce deletirious effects, serious injury or death
LD50 is the dosage (mg/kg b.w.) causing death in 50% of

exposed animals

Approximate Acute LD50


of Some Representative
Chemical Agents

Agent
Ethyl alcohol
Sodium chloride
Ferrous sulfate
Morphine sulphate
Phenobarbital sodium
Picrotoxin
Strychnine sulfate
Nicotine
d Tubocurarine
Hemicholinium-3
Tetrodotoxin
Dioxin (TCDD)
Botulinum toxin

LD50 mg/kg b.w.


10,000
4,000
1,500
900
150
5
2
1
0.5
0.2
0.10
0.001
0.00001

CLASSIFICATION OF TOXIC AGENTS


Toxic agents are classified in a variety of ways, depending on

the interest and needs of the classifier


Example:

toxic agents are discussed in terms of their target organs: liver,

kidney, hematopoietic system


Use: pesticide, solvent, food additive
Source: animal and plant toxins
Effects: cancer, mutation, liver injury

Toxin: generally refers to toxic substances that are produced

by biological systems such as plants, animals, fungi or


bacteria
Toxicant: used in speaking of toxic substances that are
produced by or are a by product of anthropogenic (humanade activities)

CHARACTERISTIC OF EXPOSURE
Route and Site of Exposure:
the route of administration can influence of toxicity of agents
Major route of exposure:

Ingestion: GI tract/ oral

Inhalation: lungs

Skin : dermal, topical, percutaneous

Bloodstream: intravenous

Ingestion

Inhalation

Intavenous

Intraperitoneal

Subcutaneous
Intramuscular

Lung

Gastrointestinal
Tract

Dermal

Portal
blood
Liver

Extracellular
fluid

Bile

Organs

Kidney

Feces

Blood and Lymph

Lung

Bladder

Alveoli

Urine

Expired air

Secretory
structures
Soft
tissues

Secretion

Bones

Fat

Duration and Frequency of Exposure:


The exposure of experimental animals to chemical into four

categories:
Acute : 24 h
Repeated exposure:

Subacute: 1 month/ less than


Subchronic: 1 3 months
Chronic : more than 3 months

INTERACTION OF CHEMICALS
The effects of two chemicals given simultaneously produce a

response that may simply be additive of their individual or may


greater or less than that expected by addition of their individual
response:
Additive: 2 + 3 = 5, ex: organo phospate insecticide
Synergistic: 2 + 2 = 20, ex: carbon tetrachloride and ethanol (both

hepatotoxic)
Potentiation: 0 + 2 = 10, isopropanol (nonhepatotoxic) and carbon
tetrachloride (hepatotoxic), the hepatotoxicity of carbon tetra
chloride is much greater
Antagonism = 2 + 4 = 3 or 4 + 0 = 1

Functional
Chemical
Dispositional
Receptor

TOLERANCE
Is a state of decreased responsiveness to a toxic effect of a

chemical resulting from prior exposure to that chemical or to a


structurally related chemical
Two major mechanism are responsible for tolerance:
Is due to a decreased amount of toxicant reaching the site where the

toxic effect is produced


Is due to a reduced responsiveness of a tissue to the chemical

DOSE RESPONSE

DOSE RESPONSE
Dose response relationship
The individual dose response relationship:
Response of an individual organism to varying doses of a chemical
A quantal dose response relationship
Distribution of response to different doses in a population of individual
organism
all or none: at any given dose, an individual in the population is classified
as either a responder or a nonresponder

Susceptibility to chemicals among individuals =

biological variation

Left: hypersusceptibility
Right: resistant

Plot the top two panels

Evaluating the Dose Response


Effective dose, ex: for anesthesia
Toxic dose: ex: effect such as liver injury

Lethal dose
TI (therapeutic index): ratio of the dose required to produce

a toxic effect and the dose needed to elicit the desired


therapeutic response

Ratio of doses of two different materials to produce an identical

response
Ratio of doses of the same material necessary to yield different
toxic effects

VARIATION IN TOXIC RESPONSE


Selectivity Toxicity:

That e chemical produces injury to one kind of living matter without


harming another form of life even though the two may exist in
intimate contact

Species Differences
basic tenet of toxicology: experimental results in animals,
when properly qualified, are applicable to human

it is important to recognize that both quantitative and


qualitative differences in response to toxic substances may
occur among different species
ex: LD50 for highly toxic dioxin differs by more than 1000
fold between guinea pigs and hamster

Individual Differences in Response

even within a species, large interindividual differences in response


to a chemical can occur because of subtle genetic differences

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