2. “All substances are
poisons;
there is none which is not
a poison.
The right dose
differentiates a poison
from a remedy.”
Paracelsus (1493-1541)
Dr.Ahmed-Refat
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WHAT IS A POISON?
3. TOXICOLOGY
Toxicology
is the study of adverse effects of chemicals
on living systems.
Adverse effects
any change from an organism’s normal
state dependent upon the concentration
of active compound at the target site for
a sufficient time.
Dr.Ahmed-Refat
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4. Branches of Toxicology
1. Clinical —treatments for poisonings and injuries
causedby xenobiotics
2. Environmental —environmentalpollutants,
effects on flora.
3. Mechanistic—cellular, biochemical and molecular
mechanisms by which chemicals cause toxic responses
4. Forensic —cause of death, legal aspects
5. Food —adverse effects of processed or natural food
components
6. Regulatory—assigns risk to substances of
5. CHEMICALS IN THE ENVIRONMENT
Roughly 70,000 different
synthetic chemicals are on the
global market;
many others are emitted as by-
products of their production,
use, or disposal
Dr.Ahmed-Refat
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6. CHEMICALS IN THE ENVIRONMENT
Production of chemicals has
increased from less than
0.15 billion kilograms (1935)
to more than
150 billion kilograms (1995)
Dr.Ahmed-Refat (FOM-TU-KSA-2014)
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7. A Small Dose of Toxicology Intro Principles of Toxicology
So Many Chemicals so Little Data
78.2% no data
21.4% some
data
0.4%
good data
www.preventingharm.org
8. A Small Dose of Toxicology Intro Principles of Toxicology
• Number of chemicals (1984)
• −Pesticides……………3,350
• −Drugs…………………1,815
• −Cosmetics…………….3,410
• −Food additives…….…8,627
9. A Small Dose of Toxicology Intro Principles of Toxicology
Why Don’t We Know More about
These Chemicals?
• Each year ~1,000 new chemicals come on line
• It costs ~ $ 2 million to do a cancer toxicology
screen on each chemical .
• The cancer toxicology screen takes ~2 years
14. MOLECULAR TARGETS CONCEPT
The toxic action= interaction of the
active form with a molecular
target within the living organism
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15. EXPOSURE
Route of Exposure
Dermal (skin)
Inhalation (lung)
Oral ingestion (Gastrointestinal)
Injection
• The route of exposure may be
important if there are tissue-
specific toxic responses.
• Toxic effects may be local or
systemic
16. ADME:
ABSORPTION, DISTRIBUTION,
METABOLISM, AND EXCRETION
The body has defenses:
Membrane barriers
passive and facilitated diffusion, active
transport
Biotransformation enzymes,
antioxidants
Elimination mechanisms
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17. ABSORPTION:
Ability of a chemical to enter the
blood (blood is in equilibrium with
tissues
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21. METABOLISM:
Make chemical agents more water
soluble and easier to excrete
decrease lipid solubility
increase ionization
Bioactivation--Biotransformation
can result in the formation of
reactive metabolites
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22. TOXICOKINETICS
A reflection of how the body
handles toxicants .
The end result of these toxicokinetic
processes is a biologically effective
dose of the toxicant.
What We do to the Chemical
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23. TOXICODYNAMICS
the molecular, biochemical, and
physiological effects of toxicants
or their metabolites in biological
systems
What the Chemical Does to Us
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26. DOSE
The amount of chemical entering the
body
This is usually given as
mg of chemical/kg of body weight =
mg/kg
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27. DOSE
The dose is dependent upon
The environmental concentration
The properties of the toxicant
The frequency of exposure
The length of exposure
The exposure pathway
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28. WHAT IS A RESPONSE?
Change from normal state
could be on the molecular, cellular, organ, or
organism level--the symptoms
Local vs. Systemic
Reversible vs. Irreversible
Immediate vs. Delayed
Graded vs. Quantal
Stochastic vs Non Stochastic
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29. DOSE-RESPONSE CURVE
Stochastic (“Random”) Model
Risk (probability) of response is a function of
dose
−Assumes no threshold
−No dose is safe
−Any dose increases the risk (not severity)
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30. DOSE-RESPONSE CURVE
Stochastic (“Random”) Model
For example, cancer
Implies that any exposure increases
the risk of cancer, with larger
exposures producing a greater risk
(but not a bigger tumor)
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32. DOSE-RESPONSE CURVE
Non-Stochastic (“Deterministic”) Model
Severity of response is a function of dose
−Assumes a threshold
−A “safe”dose exists
−Examples
−Cataractogenesis
−Mental retardation following in uteroirradiation
Chloracne
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36. Too high:Anorexia,
anemia, nose bleeds,
muscleand joint pain
SOME CHEMICALS HAVE BOTH THERAPEUTIC
AND TOXIC EFFECTS: VITAMIN A
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Dose
Adverse
response
Threshold
Too low:
Blindness,
dry skin,
increased
infections
38. BIOTRANSFORMATION
Key organs in biotransformation
LIVER (high)
Lung, Kidney, Intestine (medium)
Others (low)
Biotransformation Pathways
* Phase I--make the toxicant more water soluble
* Phase II--Links with a soluble endogenous agent
(conjugation)
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39. INDIVIDUALSUSCEPTIBILITY
--
Genetics-species, strain variation,
interindividual variations (yet still can
extrapolate between mammals--similar
biological mechanisms)
Gender (gasoline nephrotox in male mice
only)
Age--young (old too)
underdeveloped excretory mechanisms
underdeveloped biotransformation
enzymes
underdeveloped blood-brain barrier
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40. INDIVIDUAL SUSCEPTIBILITY
Age--old
changes in excretion and metabolism rates, body
fat
Nutritional status
Health conditions
Previous or Concurrent Exposures
additive --antagonistic
synergistic
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41. Evaluating Dose-Response Relationships
ED: Effective dose
(therapeutic dose of a drug)
TD: Toxic dose
(dose at which toxicity occurs)
LD: Lethal dose
(dose at which death occurs)
NOAEL: no observed adverse effect level
LOAEL: lowest observed adverse effect level
dose (mg/kg)
10-2 10-1 100 101 102 103
0
20
40
60
80
100
ED
TD
LD
50 %
response
LOAEL
NOAEL
%
response
42. Evaluating Dose-Response Relationships
ED50: dose at which 50% of population therapeutically responds.= ??
TD50: dose at which 50% of population experiences toxicity (TD50=?? mg/kg).
LD50: dose at which 50% of population dies (LD50=?? mg/kg).
dose (mg/kg)
10-2 10-1 100 101 102 103
0
20
40
60
80
100
ED
TD
LD
50 %
response
LOAEL
NOAEL
%
response
46. TOXICOLOGY- SUMMERY
Exposure + Hazard = Risk
All substances can be a poison
Dose determines the response
Pathway,Duration of Frequency of Exposure and
Chemical determine Dose
Absorption,Distribution, Metabolism & Excretion
The extent of the effect is dependent upon the
concentration of the active compound at its site of
action over time
Bioactivation:compounds to reactive metabolites
Individualvariation of the organism will affect ADME
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