Lec 6- Enviro And Health Jan 25Th

Front 1

Toxicity

Back 1

The adverse effects that a chemical
may produce.

Front 2

Dose

Back 2

The amount of a chemical that gains
access to the body.

Front 3

Exposure

Back 3

Contact providing opportunity of
obtaining a poisonous dose.


Front 4

Hazard

Back 4

The likelihood that the toxicity will be
expressed.

Front 5

Foreign chemicals: def and aka?

Back 5

are
not synthesized within the body are termed xenobiotics (Gr.Xenos meaning “strange”)*

Front 6

Xenobiotics

Back 6

may be naturally occurring chemicals produced by plants, microorganisms, or animals (including humans).

Front 7

Xenobiotics may also be?

Back 7

synthetic chemicals produced by humans.

Front 8

Poisons are xenobiotics, but not all xenobiotics are poisonous.

Back 8

Poisons are xenobiotics, but not all xenobiotics are poisonous.

Front 9

Relative Toxicity: Are all substances toxic? explain

Back 9

Yes

- All are toxic to some quantifiable degree Sugar has an LD50 of 30,000 mg/kg
The foresters favorite – ethanol has an LD50 of only 13,700 mg/kg
Even water has a recognized LD50 of slightly greater than 80,000 mg/kg

Front 10

The magnitude of risk is proportional

Back 10

o both the potency of the chemical and the extent of exposure.

Front 11

The dose makes the poison” means?

Back 11

(amount of chemical at the target site determines toxicity).

Front 12

Dose response relationship

Back 12

Definition: the association between dose (concentration) and the incidence of a defined effect in an exposed population.

Front 13

What are the two types of dose response relasionships

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1-Gradual (continuous): dose-related increase in the severity of the response. Example: percentage of enzyme inhibition.
2-Quantal (all or none): either a response or no response. Example: death, cancer, mutation.

Front 14

What are examples of ways you can be exposed to toxins:

Back 14

Ingestion (water and food) Absorption (through skin)
Injection (bite, puncture, or cut) Inhalation (air)

Front 15

Exposure to chemicals may come from many sources:

Back 15

– Environmental
– Occupational – Therapeutic – Dietary
– Accidental
– Deliberate

Front 16

How does the body prevent the actions of xenobiotics? (3)

Back 16

1) Redistribution
2) Excretion – (primarily water soluble compounds)
- kidney and liver
3) Metabolism – the major mechanism for terminating xenobiotic
activity, and is frequently the single most important determinant of the duration and intensity of toxic responses to a xenobiotic.
- LIVER, kidney, lung, GI, and others


Note: 1) and 2) are highly dependent upon 3)

Front 17

Toxicokinetics

Back 17

(from the Greek kniesis): is the study of the movement of chemicals around the body.

Front 18

Toxicodynamics

Back 18

(from the Greek dyanmos: exertion of power): processes and changes that
the chemical induce at the site of action.

Front 19

Absorption

Back 19

Process of transfer of the parent compound from the site of administration to the general circulation.
• Involvescrossingtheplasmamembrane

Front 20

• Typesofsubstancemovementacrossthemembrane:

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– Simple diffusion: by concentration gradient.
– Passive transport: by a carrier protein through plasma membrane.
– Active transport: by a carrier protein using ATP

Front 21

• Routes of absorption:

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– Gastrointisetinal (GI): oral
– Dermal: skin application – Pulmonary: inhalation

Front 22

• How to measure absorption:

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Parameters relating to absorption from extravascular (oral, dermal, inhalation) is derived from comparison of data following extravascular dose with intravenous dose .
– Radioactive labelled compound: followed up inside the body.
19

Front 23

GI tract absorption

Back 23

Occurs throughout the tract : mouth until large
intestine

However most absorption occurs in the intestine • Because of large surface area
• Blood supply
• Longer contact: food stays there for long time

Front 24

How changes GI tract absorption

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– Presence of other substances, age, diseases, pH and ionization.

Front 25

Which substances can cross the plasma membrane? easily?

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– Lipophilic compounds are easily absorbed through membrane
– If a chemical is ionized (has electric charge)===less absorption
– Compounds are most absorbed from the region of the GI tract when they are least ionized: example weak acids and weak bases:

Front 26

Ex of absorption of acids in the stomach?

Back 26

example benzoic acid.

Front 27

Absorption of bases in the intestine: ex?

Back 27

aniline:

Front 28

Respiratory route of absorption?

Back 28

• Water-soluble gases tend to be absorbed in the watery mucus of the upper respiratory tract.

Front 29

How is the absorption area of the respiratory tract determined?

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particle size:

Front 30

Which particles are absorbed where ?

Back 30

>5μm particles absorbed into the nasopharyngeal region
– 2-5 μm particles absorbed into the trancheobroncheolar region.
– < 1μm are deposited into the alveoli where they come in contact with the blood capillaries.

Front 31

Dermal absorption is the greatest cellular barrier made up of what?

Back 31

: thick layers of cells and keratin.

Front 32

• Factors influencing dermal absorption:

Back 32

Thickness and degree of keratinisation The conditions of the skin
injuries (scrapes, burns, cuts) that may remove the keratin layer of the epidermis.

Front 33

Distribution

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Is the reversible transfer of the chemical between the general circulation and the tissues.

Front 34

• Some toxicants have high affinity to tissues: explain

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– some toxins bind albumin.
– Liver and kidney contains proteins called metallothioneins...hole heavy metals (zinc and cadmium)
– Highly lipid soluble compounds can accumulate in the fat tissues (DDT)..these tissues are often referred to as Storage Depots.

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The rate the toxicant is distributed to the various tissues of the body depends on:

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– Rate of blood supply (perfusion): high: heart, lungs, kideny
– Ability of the toxicant to cross membranes (lipophilicity).
– Special physio-anatomical structures: blood brain barrier (BBB). Which allows only entry of highly lipophilic substances.

Front 36

Which substance can cross the BBB? why?

Back 36

Only highly lipid soluble materials can cross BBB..can you think of??
Organic solvents: .....solvent abuse: acetone, methane, hexane.

Front 37

biotransformation

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To convert lipid-soluble, non-polar, non-excretable forms of chemicals to water-soluble, polar forms that are excretable in bile and urine

Front 38

What 2 phases does biotransformation occur in?

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Phase I metabolism: the parent compound is hydrolyzed or oxidized to generate or expose functional groups.

Phase II (Conjugation reactions): Attachment of a larger, more hydrophilic molecule which is usually charged. Consider sugar in water

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Elimination

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Is the irreversible loss of the parent compound due to 1-excretion 2-deactivation (through biotransormation). Reflects the overall ability of the body to permanently get red of the toxins

Front 40

• Excretion happens to what chemicals?how?

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– Water soluble chemicals: kidney – volatile chemicals: lungs
– Lipid soluble: metabolism: bile
– Other routes: milk, saliva, sweat.

Front 41

• Plasma clearance factors:

Back 41

– Enzyme induction
– Liver and kidney diseases
– Inter-individual differences in hepatic enzymes or organ blood flow.

Front 42

How Xenobiotics Cause Toxicity (@the molecular level)???

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Some xenobiotics cause toxicity by disrupting normal cell functions: – Bind and damage/inhibit proteins (structural, enzymes)
– Bind and damage DNA (mutations)
– Bind and damage lipids
– React in the cell with oxygen to form
“free radicals” which damage lipid, protein,
and DNA

Front 43

Consequences of DNA damage

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Canresultinwrongbase-paring: inaccurate replication of the damaged region of the gene.
– DNAadductscommonlycausemutations (depends on the chemical and physical properties of the adduct).
– Differenttypesofmutations
– Physicaldamage(UVandionizing radiation) also cause mutations and perturbs the structure of DNA
– Mutationscaninitiatecarcinogenesisif not fixed
– Chromosomalaberrations:lesionsinthe whole chromosomes: serious

Front 44

Teratogenicity:

Back 44

birth defects

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Respiratory toxicity:

Back 45

asthma, pneumoconiosis, lung cancer

Front 46

Cardiovascular toxiccity:

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atherosclerosis, vascular spasms and blood pressure, anemia

Front 47

Neurotoxicity:

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increasing the risk of multiple sclerosis, Parkinson's disease

Front 48

Hepatoxicity:

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Liver steatosis, sinusoidal damage, liver cell death: necrosis and apoptosis, cirrhosis, liver cancer

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• Renal toxicity:

Back 49

acute renal failure and chronic renal failure

Front 50

Immunotoxicology:

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allergies (hypersensitivity), autoimmunity , immunosuppression

Front 51

Mixtures and Chemical Interactions are more realistic because?

Back 51

In the real world we are rarely exposed to a single substance. Environment is full of mixtures

Front 52

Types of Chemical Interactions?

Back 52

additive effect
synergism
Potentiation:
anatgonism

Front 53

Additive effect: def and ex?

Back 53

: the result of two or more chemical acting together:
(1+1=2)

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Synergism: def and ex?

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(multiplicative effect): the effects of two chemical together is more than the theoretical sum of their individual effects (1+1=4, 1+5=10, etc): example asbestos and cigarette smoking increase the risk of lung cancer by a factor of 40. another example: ethanol and carbon
tetrachloride (CCl4).

Front 55

Wat is the mechanism of these chemical interactions?

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usually one chemical interferes with the toxicokinetics of the other (either increase absorption or decrease metabolism and elimination).

Front 56

Potentiation: def and ex?

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when one chemical A is not toxic, but if given with chemical B it makes B much
more toxic (0+2=10)

Example isopropanol (not toxic) but increases the toxicity of CCl4

Front 57

Antagonism

Back 57

when tow chemical interferes with each other’s action (4+6=8 or 4+3=0)..