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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 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

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


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

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, 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

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
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


2008 Society of Toxicology

50

100

Population Dose-Response

Number of Individuals

Many

Resistant
Individuals

Minimal
Effect

Majority of
Individuals
Average Effect

Sensitive
Individuals

Maximal
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

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

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
2008 Society of Toxicology

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