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TOXICOKINETICS/TOXICODYNAMICS
Toxicokinetics is the quantitation of the time course of toxicants in the body during
the processes of absorption, distribution, biotransformation and excretion or
clearance of toxicants
...
The
end result of these toxicokinetic processes is a biologically effective dose of the
toxicant
...
Toxicokinetic data is best derived using radio labeled dose of the
drug
...
It is concerned with what the
body does to the toxicant
...
The fundamental parameters that define the rates and extents of
distribution and elimination are derived from data following an intravenous or oral
dose
...
The dose - The kinetics of a drug may differ from therapeutic dose

to its toxic dose
...
The concentration in the target organ - Toxicokinetics is
important in predicting the plasma concentration of a drug
...
Duration and concentration of drug at the portal of entry
2
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This means that a highly toxic drug that is poorly absorbed may
have same hazard as another with low toxicity but is highly absorbed
...
The distribution of drug within the body; where most drugs are distributed in
highly perfused organs like brain, liver and kidneys
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4
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5
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The ability of the drug to pass through cell membranes and interact with cell
constituents
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The amount and storage duration of the drug or its metabolites in the tissue
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Lead in bones is an
Example
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The rate and site of excretion; where the more rapid the excretion, the less

toxicity
it will produce
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The dose uptake into the body (absorption), Movement within the body
(distribution) conversion to toxic or non-toxics species (biotransformation),
Removal from the body (excretion)
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The dose is the total
amount of the chemical to which an organism is exposed to
...
Thus, not only
is it important to consider whether an agent is toxic,, but also the amount off that
agent that is required to cause harm
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Nature of the dose-response relationship: i
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ii
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However, variation in the response occurs in
individuals with different genetic characteristics and hence toxic responses vary

between individuals
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Example
of a dose-response (a) a toxic effect is identified and the dose required to produce
that toxic effect for each animal in a population is determined (b) the % of animals
showing this particular toxic effect will increase as the dose increases (c)(with
increasing dose, toxicity manifests and (continues to rise until there is a 100%
response
...
Toxicokinetics for non-drug chemicals (environmental and occupational
chemicals)
2
...
(i
...
how a substance enters the body and what
happens to it in the body)
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Amount and time a chemical stays at the site of absorption
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Rate of absorption
and amount absorbed
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Distribution of the chemical throughout the body
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Speed of biotransformation and nature of the metabolites formed
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Whether a
chemical can pass through cell membranes
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Whether a chemical, or its
metabolites are stored in the body
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Rate of excretion — if a chemical is
administered faster than it is excreted, it will accumulate in the body
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Absorption is
the first step of the toxicokinetics of a chemical
...
The skin, lungs and GIT may be considered as
barriers separating higher organisms from environment containing chemicals
...

•Mechanisms of crossing barriers
Absorption of a substance from the site of exposure may occur by:
1
...
2
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Active transport 4
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In general, the greater the amount of the chemical in contact with the absorbing
surface, the greater the amount of the dose that is absorbed
...
Route of exposure - a chemical may be highly absorbed from one route of
exposure,, but not from another
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Temperature - increased temperature aids
absorption through the skin
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Surface -active materials facilitate penetration
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Integrity of the absorbing surface
ROUTES OF EXPOSURE
(1) Oral exposure (GIT) An important route by which chemicals enter the body
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The main route for the intake
of many therapeutic drugs
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Children may ingest toxic chemicals
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(b) Stomach- Stomach contents are acidic and weak organic acids are absorbed
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g
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- Aspirin is lipid-soluble and enter the circulation by crossing the gastric mucosa
(c)Small intestine- Absorption of alkaline chemicals (and food) is greatest here
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- Carrier-mediated mechanisms exist
for some larger chemicals
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(2) Absorption through the skin
• Skin comes into contact with many toxic chemicals (caustics and corrosives)
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• Cells in the outer layer of the skin are resistant to chemicals, also there are no
blood vessels in the outer layer
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Factors influencing absorption of chemicals through the skin:
• Period of time skin is exposed and the concentration
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• Formulation of the chemical and its chemistry
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Chemicals absorbed by the lungs are
usually: Gases, Vapours of volatile liquids, Aerosols, Particles
(4) Eye
• Local and systemic effects can be produced by chemicals iin the atmosphere
via absorptiion at the eye
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BIODISTRIBUTION
• The way a chemical moves from the site of absorption to other parts of the body
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• Once in blood, chemicals circulate either free or bound to a plasma protein or
blood
cells
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• The chemical or its metabolites may interact with cell components
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Factors affecting the biodistribution of a chemical:
(1)Route of exposure
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(3) The
presence of structural barriers (4) Storage of chemicals in tissues
BIOTRANSFORMATION
The process by which a substance is changed from one chemical form to another
by a chemical reaction within the body, also referred to as “metabolism”
Biotransformation of a foreign chemical can be either beneficial or harmful
...

EXCRETION
• Excretion is a major determinant off the potential toxicity of a foreign chemical,
rapid excretion less toxicity
...

• Chemicals may be excreted as the parent compound or metabolites formed as a
result of metabolism
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• Many chemicals have to be biotransformed to more water-soluble products before
they can be excreted in the urine
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Processes off excretion
1
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The
filtration membrane contains large pores so small molecules readily pass into the
tubule
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Proteins and blood cells are too large to pass through the pores
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Tubular secretion: Some substances are actively transported from the blood into
the renal tubule and are thus also excreted in the urine
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Tubular reabsorption: Active------ From tubules into blood capillaries
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TOXICODYNAMICS
Toxicodynamics involves the interactions of a toxicant with a biological target and
the functional or structural alterations in a cell that can eventually lead to a toxic
effect
...
Interactions between a toxicant
and the biological target may also be more specific, where high-affinity binding
sites increase the selectivity of interactions
...
The targets are often receptors on
the cell surface or in the cytoplasm and nucleus
...
In pharmacology, pharmacodynamics is sometimes confined to
beneficial or therapeutics effects
...
Toxicodynamics seeks to define the untoward
biological response elicited by a chemical stimulus and to reveal how the chemical
brings about the response
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The mechanism of action underlying a biological
response to a chemical begins with a molecular interaction between the chemical
and a target, such as a receptor or enzyme
...
Further
physiological responses to a chemical – target interaction define the mode of action
of the chemical that shapes the observed biological response in the intact organism
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If the biological target is critical and the damage is

severe enough, irreversible injury can occur first at the molecular level, which will
translate into effects at higher levels of organization

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