© 2008 Society of Toxicology Toxicology Concepts.

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© 2008 Society of Toxicology Toxicology Concepts

Transcript of © 2008 Society of Toxicology Toxicology Concepts.

Page 1: © 2008 Society of Toxicology Toxicology Concepts.

© 2008 Society of Toxicology

Toxicology Concepts

Page 2: © 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

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© 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.

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© 2008 Society of Toxicology

Exposure

• Environmental, including home and school

• Occupational

• Therapeutic

• Dietary

• Accidental

• Deliberate

Sources of exposure to chemicals

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© 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 =

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© 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

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© 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)

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© 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

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© 2008 Society of Toxicology

All Interactions between

chemicals and biological systems follow a

Dose-Response Relationship

Dose

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© 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

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© 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.

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© 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

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© 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)

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© 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

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© 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

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© 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

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© 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

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© 2008 Society of Toxicology

Organs Respond to Chemicals in Various Ways

Blood OrgansOrgans

Desired EffectsDesired Effects

NutritiveNutritive

TherapeuticTherapeutic

Undesired EffectsUndesired Effects

ToxicToxic

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© 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

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© 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

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© 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)

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© 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

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© 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)

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© 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

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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