Introduction To Sox

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
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.
AND Spinach.
Exposure
Sources of exposure to
chemicals
Environmental, including
home and school
Occupational
Therapeutic
Dietary
Accidental
Deliberate
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
Exposure
Route of Exposure
The route (site) of exposure is an important
determinant of the ultimate dosedifferent
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
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)
Dose
THE KEY CONCEPT in Toxicology
Father of Modern Toxicology

Paracelsus1564
All things are poisonous, only the dose makes it non-poisonous.

Dose alone determines toxicity
All chemicalssynthetic or naturalhave the capacity
to be toxic
Dose
All Interactions between
chemicals and biological systems follow a
Dose-Response Relationship
Dose
Woman Dies after Water-drinking Contest: Water
Intoxication eyed in Hold Your Wee for a Wii contest Death
SACRAMENTO, CaliforniaA woman
who competed in a radio stations
contest to see how much water she
could drink without going to the
bathroom died of water intoxication,
the coroners office said Saturday.
Updated: 10:24 p.m. ET Jan 13, 2007
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.
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
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)
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
100
Effective Dose
100
80
60
ED50
40
20
1
7 10
Animals Killed (%)
Animals Sleeping (%)
The Dose Makes the Poison

100
Lethal Dose
80
60
LD50
40
20
10 20 30
Phenobarbital (mg/kg) Log Scale

50
100
Population Dose-Response
Number of Individuals
Many
Resistant
Individuals
Minimal
Effect
Majority of
Individuals
Average Effect
Sensitive
Individuals
Maximal
Effect
Few
Mild
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
Organs Respond to Chemicals in Various

Ways
Blood
Organs
Desired Effects
Nutritive
Therapeutic
Undesired Effects
Toxic
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
Some Chemicals are Partially

Converted to Products that are More Toxic
than the Parent Substance
Liver and other Organs
Activation
More Toxic Metabolic Product

Toxicological Paradigm
Exposure
Toxicokinetics
Toxicodynamics
What We do to the Chemical
What the Chemical Does to Us
Internal
Dose
Absorption
Distribution
Metabolism
Excretion
Storage
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
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
Drug Concentration (g/mL)

Plasma levels 6 hrs after oral dose
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
Identify People with normal responses
Id
en
tif
y
ch dif peo
e fe p
se mic ren le w
ns al/ t
ith
iti dru
vi
ty g
More
Sensitive
Less
Sensitive
Tools of Modern Molecular Toxicology:

Genomics and Proteomics
NH2
NH2
NH2
-COOH
+TOF MS: 24 MCA scans from Myo_tryptic.wiff

5191
5000
4500
Max. 5191.0 cou
1360.7892
1606.8892
4000
K -COOH
K -COOH
3500
3000
1938.0629
I
n
t
e
n
s
i
t
y
,
c
o
u
n
t
s
2500
2000
1500
1000
1815.9397
1378.8696
1506.9692
2316.3092
1886.0672
1271.6925 1661.8925
5001001.4584
1983.1071
1589.8688
1343.7703
1798.9216
1071.6147
2298.2643
1959.0339
2505.3460
2602.5045
0
1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000
m/z, amu

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Toxicology Concepts

2008 Society of Toxicology

Evaluation of risk embodies all

2008 Society of Toxicology

The science of Toxicology helps people make

2008 Society of Toxicology

The route of exposure may be important if there

2008 Society of Toxicology

2008 Society of Toxicology

Father of Modern Toxicology

All things are poisonous, only the dose makes it non-poisonous.

2008 Society of Toxicology

2008 Society of Toxicology

Updated: 10:24 p.m. ET Jan 13, 2007

2008 Society of Toxicology

A key concept in Toxicology is the quantitative

The magnitude of the effect of a xenobiotic is

In any given population, there will be a range of

2008 Society of Toxicology

2008 Society of Toxicology

2008 Society of Toxicology

Animals Killed (%)

Animals Sleeping (%)

The Dose Makes the Poison

Phenobarbital (mg/kg) Log Scale

Response to SAME dose

Some chemicals have both therapeutic

Too high: Anorexia,

Organs Respond to Chemicals in Various

2008 Society of Toxicology

Some Chemicals Are Transformed by

2008 Society of Toxicology

Some Chemicals are Partially

More Toxic Metabolic Product

What We do to the Chemical

What the Chemical Does to Us

The LIVER is the

Harmful Side Effects

Drug Concentration (g/mL)

Identify People with normal responses

Tools of Modern Molecular Toxicology:

+TOF MS: 24 MCA scans from Myo_tryptic.wiff

Max. 5191.0 cou

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