Environmental toxicology

1. ENVIRONMENTAL TOXICOLOGY
Basic Concepts
Dr Ahmed-Refat A.G. Refat
FOM-TU-KSA-2014
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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)
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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.
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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
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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

10. THE TOXICOLOGICAL PROCESS
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11. THE TOXICOLOGICAL PROCESS
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12. Dr.Ahmed-Refat
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13. THE TOXICOLOGICAL PROCESS
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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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18. Distribution:
Storage and Binding
•Storage in Adipose tissue--
•Storage in Bone-
•Binding to Plasma proteins.
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19. TARGET ORGANS:
 Liver--high blood flow, oxidative reactions
 Kidney--high blood flow, concentrates
chemicals
 Lung--high blood flow, site of exposure
 Neurons--oxygen dependent, irreversible
damage
 Myocardium--oxygen dependent
 Bone marrow, intestinal mucosa--rapid
divide
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20. EXCRETION:
 Urinary excretion
 Exhalation
 Biliary Excretion via Fecal
Excretion
 Milk Sweat Saliva
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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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24. EXPOSURE
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Time of Exposure
• How long an organism is exposed to a
chemical is important
Duration and frequency contribute
to dose. Both may alter toxic effects

25. Exposure: Duration
Acute < 24hr usually 1 exposure
Subacute 1 month repeated doses
Subchronic 1-3mo repeated doses
Chronic > 3mo repeated doses
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Dr.Ahmed-Refat

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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31. STOCHASTIC (“RANDOM”) MODEL
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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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33. EXAMPLES OF TOXICANTS:
CHEMICALSTHAT CAN CAUSE HARM
Dioxin poisoning
→ facial scarring (chloracne)
Hg in fish
→ brain damage
www.seco.noaa.gov

34. DOSE-RESPONSE RELATIONSHIP
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Phenobarbital (mg/kg) Log Scale
ED50
LD50
Effective Dose Lethal Dose
100
60
80
40
20
100
60
80
40
20
10 20 30 50 100
1 2 3 5 7 10

35. POPULATION DOSE-RESPONSE
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Mild Extreme
Many
Few
Number
of
Individuals
Response to SAME dose
Sensitive
Individuals
Maximal
Effect
Resistant
Individuals
Minimal
Effect
Majorityof
Individuals
Average Effect

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

37. Toxic Potency
Agent LD50 (mg/kg)
Ethyl alcohol 10,000
Sodium chloride 4,000
BHA/BHT (antioxidants) 2,000
Morphine sulfate 900
Caffeine 200
Nicotine 1
Curare 0.5
Shellfish toxin 0.01
sarin 0.001
Botulinum toxin 0.00001
slight
moderate
high
Extremely high
(<1 mg/kg)

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

43. EXPOSURE
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1. Environmental, including
home and school
2. Occupational
3. Therapeutic
4. Dietary
5. Accidental
6. Deliberate
Sources of exposure to
chemicals

44. DOSE
Determines Whether a Chemical Will Be Beneficial
or Poisonous
Beneficial Dose Toxic Dose
Aspirin 300 – 1,000 mg 1,000 – 30,000 mg
Vitamin A 5000 units/day 50,000 units/day
Oxygen 20% (Air) 50 – 80% (Air)

45. Dr.Ahmed-Refat
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TOXICOLOGICAL PARADIGM
Exposure
Internal
Dose
Biologically
Effective
Dose
Early
Biological
Effect
Altered
Structure &
Function
Disease
Absorption
Distribution
Metabolism
Excretion
Storage
Toxicokinetics Toxicodynamics
What We do to the Chemical What the Chemical Does to Us
Susceptibilityand
ModifyingFactors
(Genetics and Nutritional Status)

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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