© 2008 Society of Toxicology Toxicology Concepts
© 2008 Society of Toxicology
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…….
AND Spinach.
© 2008 Society of Toxicology
Exposure
• Environmental, including home and school
• Occupational
• Therapeutic
• Dietary
• Accidental
• Deliberate
Sources of exposure to chemicals
© 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
Father of Modern ToxicologyFather of Modern Toxicology Paracelsus——1564
“All things are poisonous, only the dose makes it non-poisonous.”
Dose alone determines toxicityAll chemicals—synthetic or natural—have the capacity
to be toxic
Dose THE KEY CONCEPT in Toxicology
© 2008 Society of Toxicology
All Interactions between
chemicals and biological systems follow a
Dose-Response Relationship
Dose
© 2008 Society of Toxicology
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.
Woman Dies after Water-drinking Contest: WaterIntoxication eyed in ‘Hold Your Wee for a Wii’ contest Death
Updated: 10:24 p.m. ET Jan 13, 2007
Dose
© 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”
0
1.0Maximum Response
EC50
Arithmetic Scale
0 20 40 6080 100Concentration
0.5
1.0
0
Maximum Response
EC50
Approx.Linear
Range
0.1 1.0 10 100
Logarithmic Scale
0.5
Concentration
Rate
Threshold
© 2008 Society of Toxicology
Dose-Response Relationship“The Dose Makes the Poison”
An
ima
ls S
lee
pin
g (
%)
Phenobarbital (mg/kg) Log Scale
An
ima
ls K
ille
d (
%)
ED50LD50
Effective Dose Lethal Dose100
60
80
40
20
100
60
80
40
20
10 20 30 50 1001 2 3 5 7 10
© 2008 Society of Toxicology
Population Dose-Response
Mild Extreme
Many
Few
Nu
mb
er o
f In
div
idu
als
Response to SAME dose
Sensitive Individuals
Maximal
Effect
Resistant Individuals
Minimal
Effect
Majority of Individuals
Average Effect
© 2008 Society of Toxicology
Too high: Anorexia, anemia, nose bleeds, muscle and joint pain
Some chemicals have both therapeutic and toxic effects: Vitamin A
Dose
Adv
erse
res
pons
e
Threshold
Too low: Blindness, dry skin, increased infections
© 2008 Society of Toxicology
Organs Respond to Chemicals in Various Ways
Blood OrgansOrgans
Desired EffectsDesired Effects
NutritiveNutritive
TherapeuticTherapeutic
Undesired EffectsUndesired Effects
ToxicToxic
© 2008 Society of Toxicology
Some Chemicals Are Transformed by the Body (Metabolized) to Aid Excretion
Liver and other OrgansLiver and other Organs
DetoxicationDetoxication
Less Toxic Metabolic ProductLess Toxic Metabolic Product
LiverLiver
Feces / BileFeces / Bile
LungLungKidneyKidney
Expired AirExpired AirUrineUrine
© 2008 Society of Toxicology
Some Chemicals are Partially Converted to Products that are More Toxic
than the Parent Substance
Liver and other OrgansLiver and other Organs
ActivationActivation
More Toxic Metabolic ProductMore Toxic Metabolic Product
© 2008 Society of Toxicology
Toxicological Paradigm
ExposureInternalDose
Biologically Effective Dose
Early Biological Effect
Altered Structure & Function
Disease
AbsorptionDistributionMetabolismExcretionStorage
Toxicokinetics Toxicodynamics
What We do to the Chemical What the Chemical Does to Us
Susceptibility andModifying Factors
(Genetics and Nutritional Status)
© 2008 Society of Toxicology
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 The LIVER is the
primary site of metabolism
Liver
Biotransformation occurs in the Liver, kidney, lung, gastrointestinal track, and other organs
© 2008 Society of Toxicology
Pharmacogenetics of Metabolism
0 2 4 6 8 10 120
5
10
15
20
25R
es
po
ns
e F
req
ue
nc
y(#
of i
ndiv
idua
ls)
Plasma levels 6 hrs after oral dose
Fast Metabolizers
Harmful Side Effects
Slow Metabolizers
(elevated plasma levels)
Drug Concentration (g/mL)
© 2008 Society of Toxicology
The emerging field of “Pharmacogenomics” or “Toxicogenomics” offers the potential to identify and protect subsets of people predisposed to toxicity from chemicals or drugs
Typical Population
Identify People with “normal” responses
Identify people with
different
chemical/drug
sensitivity
More Sensitive
Less Sensitive
Tools of Modern Molecular Toxicology:Genomics and Proteomics
NH2
NH2
NH2
-COOHR
K -COOH
-COOHK
+TOF MS: 24 MCA scans from Myo_tryptic.wiff Max. 5191.0 counts.
1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000m/z, amu
0
500
1000
1500
2000
2500
3000
3500
4000
4500
50005191
Intensity, counts
1360.7892
1606.8892
1938.0629
1815.9397
1378.8696
2316.30921506.9692
1886.06721271.6925 1661.89251001.4584 1983.10711589.86881343.7703 1798.92161071.6147 2298.26431959.0339 2505.3460 2602.5045