Understanding Toxicology Principles

PRINCIPLES OF
TOXICOLOGY
PRINCIPLES of TOXICOLOGY
OBJECTIVES:
To explain the general nature of toxic
action of substances
To describe the nature of toxic action and
the effects brought about by chemicals
To explain the potential stages in the
development of toxicity
Introduction to Toxicology
Toxicology is the study of the adverse

effects of chemicals on living organisms.
Toxicologist- one who is trained to

examine the nature of those effects
( cellular, biochemical, and molecular
mechanisms of action) and assess the
probability of their occurrence
BRANCHES OF
TOXICOLOGY
Clinical toxicology
Effects of substances to patients
Experimental
Effects of chemicals in the biological
system
Measures laboratory parameters
Descriptive toxicology
Toxicity testing
Provide information for safety evaluation
and regulatory requirements
SET LIMITS
Mechanistic toxicology
Mechanism of action or MOA of
poisons
Data may be useful in the design and
production of safer chemicals and in
rational therapy for chemical poisoning
and treatment of disease
Data is useful in demonstrating that an
adverse outcome observed in laboratory
animals is directly relevant to humans
Regulatory toxicology
Involved in the establishment of standards

for the amount of chemicals permitted in
foods, drugs, air, industrial atmosphere and
drinking water
Environmental toxicology
Studying the impacts of chemicals on non

human organisms such as fish, birds,
terrestrial animals and plants
10
Forensic toxicology
Medico-legal cases of poisoning and

intoxication
11
Paracelsus
All substances are poisons;
there is none which is not a
poison.
The right dose differentiates
a poison from a remedy.
Paracelsus (1493-1541)
12
An Individual View
The sensitivity of the individual differentiates a
poison from a remedy. The fundamental
principle of toxicology is the individuals
response to a dose.
S. G. Gilbert (1997)
13
Poison
Any agent that may cause harm or serious
injury
14
every known chemical has the potential

to produce injury or death if it is present in
a sufficient amount
15
Dose
The amount of chemical entering the body
This is usually given as
mg of chemical/kg of body weight = mg/kg
The dose is dependent upon
* The environmental concentration
* The properties of the toxicant
* The frequency of exposure
* The length of exposure
* The exposure pathway
16
Dose-Response Relationship:
As the dose of a toxicant increases,
so does the response.
4
RESPONSE
0-1 NOAEL
2-3 Linear Range
4 Maximum Response
DOSE
DOSE DETERMINES THE BIOLOGICAL
RESPONSE
17
Dose response assumptions

response
is due to chemical administered

the response is related to the dose
there is a receptor site with which the
chemical interacts
the degree of response is related to the
concentration at the site
the concentration at the site is related
to the dose administered
has a quantifiable method of measuring and a
precise means of expressing the toxicity
18
Exposure: Pathways
Routes and Sites of Exposure
Ingestion (Gastrointestinal Tract)

Inhalation (Lungs)
Dermal/Topical (Skin)
Injection
intravenous, intramuscular, intraperitoneal
19
Rapidity of response with respect to route

of exposure
Intravenous
Inhalation
Intraperitoneal
Subcutaneous
Intramuscular
Intradermal
Topical
20
Exposure: Duration
Acute
Subacute
Subchronic
Chronic
< 24hr
usually 1 exposure
1 month repeated doses
1-3mo
repeated doses
> 3mo
repeated doses
Over time, the amount of chemical in the

body can build up, it can redistribute, or it
can overwhelm repair and removal
mechanisms
21
Toxins = toxic substances

produced naturally
22
Toxicants = toxic substances that are

produced or a by-product of
human activities
23
Adverse effects
any change from an organisms normal state
dependent upon the concentration of active
compound at the target site for a sufficient
time.
24
Tolerance
state
of decreased responsiveness to a
toxic effect of a chemical, resulting from
previous exposure
dispositional tolerance; a decreased amount of
drug reaching the site
cellular; reduced responsiveness of a tissue
25
Toxicity
describes
the degree to which a

substance is poisonous or can cause
injury.
26
Major factors that influence

toxicity
route
of administration
duration and frequency of exposure
dose or concentration
shape and structure of the chemical itself,
and individual human factors.
27
28
What is toxicodynamics ?
It examines the mechanism by which toxicants

produce unique cellular effects within the
organism
Mechanism of toxic action
The alteration to the cells plasma membrane,

organelles, nucleus, cytoplasm, enzyme
systems, biosynthetic pathways, development
or reproduction
29
1. Toxic action of a drug is not necessarily

an exaggeration of its therapeutic action.
2. One toxicant may exert several mechanisms
of toxic action.
3. The toxic action may be brought about by the
parent compound and/or its metabolites.
4. The mechanisms of toxic action in acute
exposure may differ from those in chronic
exposure.
5. Intensity of a toxic effect depends primarily on
the concentration and persistence of the ultimate
toxicant at its site of action.
30
1. Allergic Reactions
Chemical allergy : immunologically
mediated adverse reaction to a
chemical or to structurally
similar one
31
2. Idiosyncratic Reactions:
Chemical idiosyncrasy : refers to a
genetically determined abnormal
reactivity to a chemical; the
response observed may take the
form of extreme sensitivity to low
doses or extreme insensitivity to
high doses of a chemical
E.g. Nitrites :
deficiency in NADH-methemoglobin reductase
32
3. Immediate vs. Delayed Toxicity:

Immediate : occurs or develops
rapidly after a single administration
of a substance
Delayed: occurs after a lapse of some
Time (months or years)
33
4. Reversible vs. Irreversible Toxic Effects:

E.g.
Reversible: injury to the liver by

paracetamol
Irreversible: injury to the CNS by
ethanol
34
5. Local vs. Systemic Toxicity:

Local : site of first contact between
biological system and toxicant
E.g. Caustics skin, gastrointestinal mucosa
Chlorine gas lung tissue
Systemic: absorption and distribution of

toxicant from its entry point to a distant
site at which deleterious effects are
produced
E.g. Caustics (phenol) kidney damage
35
th edition
CasarettPRINCIPLES
& Doulls,of7TOXICOLOGY
36
TOXICATION
Biotransformation to
harmful products
E.g. Ethylene glycol converted to

oxalic acid which produces
acidosis and hypercalcemia
37
Non-covalent binding
Covalent binding
Electron transfer
Enzymatic reaction
38
Third step: Alteration of regulatory

or maintenance function of the cell
39
CELLULAR REGULATION
1. Dysregulation of gene expression
Dysregulation of transcription
40
2. Dysregulation of on-going cellular activity

Alteration
in neurotransmitter levels
Methamphetamine/amphetamine increases release

and inhibit reuptake of norepinephrine, dopamine
and serotonin
Organophosphates decrease hydrolysis of acetylcholine
41

Toxicant-neurotransmitter receptor interaction
INHIBITION
Atropine & atropine-like drugs produce inhibitory
effect on the muscarinic receptors (M2 and M3)
Increased heart rate

Decreased bowel sounds
Decreased salivation
Decreased perspiration
STIMULATION
Benzodiazepine stimulating GABA A receptor
Sedation
42

Toxicant-signal transducer interactions
DDT, pyrethroids act on
Voltage-gated Na+ channels
Neuronal activation
Overexcitation
Convulsion
43
2. Dysregulation of
on-going cellular activity
Enzyme reactions
Enzyme Inhibition
Pyridoxine kinase
Glutamic acid decarboxylase
Monoamine oxidase
Nicotinamide adenine
dinucleotide (NAD) (co-enzyme)
EFFECTS:
Seizure
Acidosis
Increased sympathetic
activity
44
CELLULAR MAINTENANCE
1. Impaired Internal Maintenance
IMPAIRED ATP SYNTHESIS
Inhibition of hydrogen
delivery to ETC (1)
(fluoroacetate inhibits
aconitase enzyme)
Inhibition of electron
transport complexes (2)
(Cyanide, CO inhibits
cytochrome oxidase)
Inhibition of oxygen
delivery to electron
transport chain (3)
(CO, hydrogen sulfide,
nitrites)
Inibition of ADP
phosporylation (4)
(DDT & chlordecone
inhibit ATP synthase )
45
CELLULAR MAINTENANCE
1. Impaired Internal Maintenance
Impaired membrane function

Ethanol and organic solvents increase membrane fluidity
Lipid solvents destroy plasma membrane
Hydrocarbons destroy lysosomal membranes
2. Impaired External Maintenance

Toxicities interfering with cells specialized to provide
support to other cells, tissues or whole organism
Inhibition of hepatic synthesis of coagulation factors by
coumarin
46
REPAIR
Molecular
Protein
Cellular
DNA
Tissue
Apoptosis
Proliferation
Lipid
Cells
ECM
Repair Mechanisms
47
Tissue necrosis
Fibrosis
Cancer
48
DYSREPAIR
Failure of DNA repair

Failure of apoptosis
Failure to terminate
cell proliferation
49
SIGNIFICANCE OF TOXICODYNAMICS:
Choice of antidotal therapy

Determine magnitude and
extent of toxicity
More effective and adequate
treatment plan
50
51
Study of how a substance gets into the

body and what happens to it in the body
Modeling and mathematical description
of the time course of disposition of
toxicants in the whole organism
52
Toxicokinetics
Only the absorbed dose that makes it to the target organ is capable
of producing an effect
Xenobiotic
Excretion
The effect which a chemical produces is not only

dependent on the dose administered but more on
the concentration of the chemical in the target
organ.
The concentration in turn depends on the
disposition of the chemical.
The kinetics of a chemical/drug may differ from
therapeutic dose to its toxic dose.
The study of toxicokinetics is important in
predicting plasma concentration of a chemical.
54
A result of a number of opposing

actions
Some promotes delivery of the
Toxicant towards the target
Others promote toxicant delivery

Away from the target
The net effect determines how

much of the toxicant
makes it to its site of action
55
Concentration
at site of action
Intensity of
toxic action
Duration of the
Ultimate
Toxicant
At Its Site of
Action
The Ultimate Toxicant is the species that interacts

with the target or critically modifies the biological
microenvironment
56
The ultimate toxicant can be:

The parent compound
A metabolite of the parent
A reactive Oxygen or Nitrogen species
An endogenous compound
57
FOUR PROCESSES IN TOXICOKINETICS

ABSORPTION is the process by which a chemical enters
the body
DISTRIBUTION is the stage when a substance moves

from the site of entry to other organs/areas of the body
METABOLISM is when the body transforms the chemical

into metabolites
EXCRETION is the process wherein the parent chemical

and its metabolites leave the body
58
Absorption, Distribution,
Metabolism, and Excretion
Once a living organism has been exposed
to a toxicant, the compound must get into
the body and to its target site in an active
form in order to cause an adverse effect.
The body has defenses:
Membrane barriers
passive and facilitated diffusion, active transport
Biotransformation enzymes, antioxidants

Elimination mechanisms
FACTORS AFFECTING KINETIC PROCESSES

Duration and concentration at the portal of entry
the higher the concentration, the greater will the damage be
Rate and amount of chemical absorbed

rate of absorption is slow and the amount absorbed is small,
the toxicity will be low
Distribution of the toxicant within the body
most of the toxicants are distributed in highly perfused
organs which have vital functions such as the brain
and the kidneys.
the organ in which a chemical is most highly concentrated
is not necessarily the organ where most tissue
damage occurs.
60
FACTORS AFFECTING KINETIC PROCESSES

Efficiency of biotransformation and nature of metabolites
a chemical maybe converted to a toxic metabolite which is

more toxic than the parent compound
Ability of the chemical or its metabolites to pass through
cell membranes and come into contact with specific cell
components
a chemical can pass through the placenta or the blood brain
barrier
Amount and duration of storage of the chemical or its
metabolites in body tissues
some chemicals are stored in body tissues for a long period
of time and would produce its effect long after the
initial exposure
61
PRESYSTEMIC ELIMINATION
First pass effect
DISTRIBUTION AWAY FROM THE TARGET SITE

Binding to plasma proteins because protein-bound chemicals
do not exert toxic action
Specialized barriers such as blood-brain barrier which prevent
entry of hydrophilic chemicals into the brain
Storage sites which are not target sites of chemicals and
where the chemicals are highly concentrated
Association with intracellular binding proteins which are
non-target intracellular sites
Export from cells wherein chemicals are transported back into the
extracellular space
62
DETOXIFICATION
Biotransformation of chemical prevents its formation I
nto ultimate toxic metabolites and enhances
its elimination
EXCRETION
The liver and the kidneys can remove efficiently highly
hydrophilic, usually ionized chemicals such as weak
acids and bases. Other processes include the bile,
gastrointestinal tract and the breastmilk.
63
Involves the movement of chemcials

across cell membranes
Phospholipid bilayer
64
Factors affecting gastrointestinal absorption of drugs/

chemicals in their toxic states
Type of cells at the specific site
Contact time
pH of the stomach and small intestine
Concentration of the drug/chemical at
absorption site
Presence of food or binding substances
Rate of gastric emptying
Gastrointestinal motility
Large absorbing surface of the small
intestines
Blood flow to the site
Intestinal microflora and GI enzymes
General condition of the patient
Product formulation
65
Solubility of the chemical in

the blood
(blood/gas coefficient)
If low, rate of transfer from alveoli to
blood is dependent on perfusion
If high, rate of transfer from alveoli to
blood is dependent on ventilation
Particle size
Water solubility
66
Condition of the skin

Body region
Lipid solubility
67
Movement of chemicals throughout

the body within the bloodstream
68
Blood flow/perfusion limitation

Permeability limitation
Capillary membrane passage
Cell membrane passage
Apparent volume of distribution
Protein binding
Effect of pH
Age
Tissue reservoir/depots
Plasma proteins
Liver and kidneys
Fat
Bone
69
Process by which the body alters

chemicals, typically for energy
production
Biotransformation
process by which both endogenous,
and exogenous substances that enter
the body are changed from hydrophobic to
hydrophilic molecules to facilitate elimination.
70
The highest capacity

for biotransformation
is the liver.
71
Metabolism =
Toxification /Detoxification
Toxication = increase in toxicity
Detoxification = decrease in toxicity
72
Toxication
Change in
Structure increases
interaction with
target molecule
Changes in general
reactivity lead to
the formation of
electrophiles
free radicals
nucleophiles
73
Detoxication
To be eliminated from the body more
efficiently must be hydrophilic and
ionized
Compounds with no functional groups
Phase I - oxidation via CYP450

Phase II - addition of endogenous acid
(conjugation)
Product: hydrophilic organic acids

Electrophiles conjugation with
glutathione a thiol nucleophile
74
Phase I reactions
Oxidation, reduction,
hydrolysis, hydration
Phase II reactions
Glucuronidation,
sulfation
TOXICANT
PHASE I
PRIMARY PRODUCT
PHASE II
SECONDARY
PRODUCT
ELIMINATION FROM BODY
75
When does detoxication fail?

Toxicants overwhelm the detoxication processes
Reactive toxicants deactivate a detoxicating
enzyme
Conjugation reactions are reversed
Reactive degradation products are formed by
detoxicating enzymes
76
Age
Sex
Pharmacogenetic factors
Pregnancy
Nutritional status/ body size
and weight
Disease states
Bioactivation
Enzyme induction/inhibition
Changes in kinetic mechanisms
77
Process by which the body

separates and discharges wastes
or toxic substances from the
body
78
Most important organ

for excretion is the kidney.
Other routes:
Fecal
Respiratory
Cerebrospinal fluid
Milk
Sweat
Saliva
79
Age
Disease states
Rate of excretion
Enterohepatic recirculation
Ion trapping
80
Phenomenon by which drugs emptied

through the bile into the small intestine can
be reabsorbed from the intestinal lumen into
systemic circulation. When reaching the
distal ileum, bacterial flora convert the
parent drug and its active metabolites back
into lipophilic states
81
Removal of Chemicals from the

body
Primary Structures:
Kidney
Glomerular filtration
Tubular excretion
Liver
Usually water soluble and ionic, weak acids and bases

No effective removal of lipophilic, persistent molecules
Some volatiles and non-reactives may leave via the
lung
82
Retention of Chemicals in the Body

In the renal tubule, toxicants can be
reabsorbed prior to excretion:
In the GI tract, compounds secreted
as ionics can be modified by gut
bacteria then reabsorbed
Enterohepatic Recirculation
83
Aspirin
Carbamazepine
Dapsone
Digoxin
Methamphetamine
Paracetamol
Phencyclidine
Phenothiazine
Phenobarbital
Phenytoin
Quinine
Rifampicin
Salicylates
Theophylline
Anticoagulants
Naphthalene
Organochlorine
pesticides
84
Winston Churchill
85

Understanding Toxicology Principles

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Understanding Toxicology Principles

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PRINCIPLES OF

Toxicology is the study of the adverse

Toxicologist- one who is trained to

Involved in the establishment of standards

Studying the impacts of chemicals on non

Medico-legal cases of poisoning and

every known chemical has the potential

Dose response assumptions

is due to chemical administered

Routes and Sites of Exposure

Ingestion (Gastrointestinal Tract)

Rapidity of response with respect to route

Over time, the amount of chemical in the

Toxins = toxic substances

Toxicants = toxic substances that are

the degree to which a

Major factors that influence

It examines the mechanism by which toxicants

Mechanism of toxic action

The alteration to the cells plasma membrane,

1. Toxic action of a drug is not necessarily

3. Immediate vs. Delayed Toxicity:

4. Reversible vs. Irreversible Toxic Effects:

Reversible: injury to the liver by

5. Local vs. Systemic Toxicity:

Systemic: absorption and distribution of

E.g. Ethylene glycol converted to

Third step: Alteration of regulatory

2. Dysregulation of on-going cellular activity

Methamphetamine/amphetamine increases release

Organophosphates decrease hydrolysis of acetylcholine

2. Dysregulation of on-going cellular activity

Increased heart rate

2. Dysregulation of on-going cellular activity

1. Impaired Internal Maintenance

Impaired membrane function

2. Impaired External Maintenance

Failure of DNA repair

Choice of antidotal therapy

Study of how a substance gets into the

The effect which a chemical produces is not only

A result of a number of opposing

Others promote toxicant delivery

The net effect determines how

The Ultimate Toxicant is the species that interacts

The ultimate toxicant can be:

FOUR PROCESSES IN TOXICOKINETICS

DISTRIBUTION is the stage when a substance moves

METABOLISM is when the body transforms the chemical

EXCRETION is the process wherein the parent chemical

Biotransformation enzymes, antioxidants

FACTORS AFFECTING KINETIC PROCESSES

the higher the concentration, the greater will the damage be

Rate and amount of chemical absorbed

FACTORS AFFECTING KINETIC PROCESSES

a chemical maybe converted to a toxic metabolite which is

DISTRIBUTION AWAY FROM THE TARGET SITE

Involves the movement of chemcials

Factors affecting gastrointestinal absorption of drugs/

Solubility of the chemical in

Condition of the skin

Movement of chemicals throughout

Blood flow/perfusion limitation