Toxicology Concepts
© 2008 Society of Toxicology
Risk
The likelihood of injury or
disease resulting from
exposure to a potential hazard
Evaluation of risk embodies all
the basic concepts of toxicology
© 2008 Society of Toxicology
The science of Toxicology helps people make
informed decisions and balance
RISKS vs. BENEFITS
The study found the
highest levels of
pesticide residues in
peaches, apples,
pears…….
© 2008 Society of Toxicology
AND Spinach.
Exposure
Sources of exposure to
chemicals
• Environmental, including
home and school
• Occupational
• Therapeutic
• Dietary
• Accidental
• Deliberate
© 2008 Society of Toxicology
Exposure
• In order for a chemical to produce a biological effect, it must first
reach a target individual (exposure pathway).
• Then the chemical must reach a target site within the body
(toxicokinetics).
• Toxicity is a function of the effective dose (how much) of a
foreign chemical (xenobiotic) at its target site, integrated over
time (how long).
• Individual factors such as body weight will influence the dose at
the target site
X
© 2008 Society of Toxicology
=
Exposure
Route of Exposure
• The route (site) of exposure is an important
determinant of the ultimate dose—different
routes may result in different rates of
absorption.
– 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
© 2008 Society of Toxicology
Exposure
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.
– Acute Exposure = usually entails a
single exposure
– Chronic Exposures = multiple
exposures over time (frequency)
© 2008 Society of Toxicology
Dose
THE KEY CONCEPT in Toxicology
Father of Modern Toxicology
Paracelsus—1564
“All things are poisonous, only the dose makes it nonpoisonous.”
Dose alone determines toxicity
All chemicals—synthetic or natural—have the capacity
to be toxic
© 2008 Society of Toxicology
Dose
All Interactions between
chemicals and biological systems follow a
Dose-Response Relationship
© 2008 Society of Toxicology
Dose
Woman Dies after Water-drinking Contest: Water
Intoxication eyed in ‘Hold Your Wee for a Wii’ contest Death
SACRAMENTO, California—A woman
who competed in a radio station’s
contest to see how much water she
could drink without going to the
bathroom died of water intoxication,
the coroner’s office said Saturday.
Updated: 10:24 p.m. ET Jan 13, 2007
© 2008 Society of Toxicology
Dose-Response Relationship
•
A key concept in Toxicology is the quantitative
relationship between the concentration of a
xenobiotic in the body and the magnitude of
the biological effect it produces.
•
The magnitude of the effect of a xenobiotic is
usually a function of the amount of xenobiotic
to which a person is exposed (i.e., “The Dose
Makes the Poison”).
•
In any given population, there will be a range
of sensitivities to a xenobiotic. It is extremely
useful to know what is the average sensitivity
of a population to a xenobiotic, and what the
average dose required to elicit a toxic response
will be.
© 2008 Society of Toxicology
Dose
• The magnitude of the toxic response is
proportional to the concentration (how much)
of the chemical at the target site.
• The concentration of a chemical at the target
site is proportional to the dose.
• Four important processes control the amount
of a chemical that reaches the target site.
– Absorption
– Tissue distribution
– Metabolism
– Excretion
© 2008 Society of Toxicology
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)
© 2008 Society of Toxicology
Dose-Response Curves
“The Dose Makes the Poison”
Maximum Response
1.0
1.0
Maximum Response
Rate
0.5
0.5
Threshold
EC50
0
0
Approx.
Linear
Range
20 40 60 80 100
EC50
0
0.1
1.0
10
Concentration
Concentration
Arithmetic Scale
Logarithmic Scale
© 2008 Society of Toxicology
100
Dose-Response Relationship
“The Dose Makes the Poison”
Effective Dose
100
100
80
80
60
60
ED50
40
Lethal Dose
LD50
40
20
20
1
2
3
5
7 10
10 20 30
Phenobarbital (mg/kg) Log Scale
© 2008 Society of Toxicology
50
100
Population Dose-Response
Number of Individuals
Many
Resistant
Individuals
Majority of
Individuals
Sensitive
Individuals
Average Effect
Maximal
Effect
Minimal
Effect
Few
Mild
© 2008 Society of Toxicology
Response to SAME dose
Extreme
Adverse response
Some chemicals have both therapeutic
and toxic effects: Vitamin A
Too low:
Blindness,
dry skin,
increased
infections
Too high: Anorexia,
anemia, nose bleeds,
muscle and joint pain
Threshold
Dose
© 2008 Society of Toxicology
Organs Respond to Chemicals in
Various Ways
Blood
Organs
Desired Effects
Nutritive
Therapeutic
Undesired Effects
Toxic
© 2008 Society of Toxicology
Some Chemicals Are Transformed by
the Body (Metabolized) to Aid Excretion
Liver and other Organs
Detoxication
Less Toxic Metabolic Product
Kidney
Liver
Lung
Urine
Feces / Bile
Expired Air
© 2008 Society of Toxicology
Some Chemicals are Partially
Converted to Products that are More Toxic
than the Parent Substance
Liver and other Organs
Activation
More Toxic Metabolic Product
© 2008 Society of Toxicology
Toxicological Paradigm
Exposure
Toxicokinetics
Toxicodynamics
What We do to the Chemical
What the Chemical Does to Us
Internal
Dose
Absorption
Distribution
Metabolism
Excretion
Storage
© 2008 Society of Toxicology
Biologically
Effective
Dose
Early
Biological
Effect
Altered
Structure &
Function
Susceptibility and
Modifying Factors
(Genetics and Nutritional Status)
Disease
Biotransformation
Metabolism
• major mechanism for
terminating the biological
activity of chemicals
• frequently the single most
important determinant of the
duration and intensity of the
pharmacological response to a
chemical
Biotransformation occurs in the
Liver, kidney, lung, gastrointestinal
track, and other organs
© 2008 Society of Toxicology
Liver
The LIVER is the
primary site of
metabolism
Pharmacogenetics of Metabolism
Fast Metabolizers
20
Harmful Side Effects
(# of individuals)
Response Frequency
25
15
Slow Metabolizers
10
(elevated plasma levels)
5
0
0
2
4
6
8
Drug Concentration (g/mL)
Plasma levels 6 hrs after oral dose
© 2008 Society of Toxicology
10
12
Typical Population
The emerging field of
“Pharmacogenomics” or
“Toxicogenomics” offers
the potential to identify and protect
subsets of people predisposed to
toxicity from chemicals or drugs
Less
Sensitive
Identify People with “normal” responses
More
Sensitive
© 2008 Society of Toxicology
Tools of Modern Molecular Toxicology:
Genomics and Proteomics
+TOF MS: 24 MCA scans from Myo_tryptic.wiff
NH2
R
-COOH
4500
1606.8892
4000
K -COOH
In te n s ity , c o u n ts
NH2
Max. 5191.0 counts.
1360.7892
5191
5000
3500
3000
1938.0629
2500
2000
NH2
K -COOH
1815.9397
1378.8696
1500
1000
500
2316.3092
1506.9692
1271.6925
1001.4584
1343.7703
1071.6147
0
1000
1200
1400
1661.8925
1589.8688
1600
1886.0672
1983.1071
1798.9216
1800
1959.0339
2000
m/z, amu
2298.2643
2200
2505.3460
2400
2600
2602.5045
2800
3000