TOXICOKINETICS 1

8/8/2019 TOXICOKINETICS 1

1/34

AZIZAN HADI SAAT

DEPARTMENT OF COMMUNITY HEALTH

UPM


2/34

FACTORS AFFECTING AN INDIVIDUAL

RESPONSE TO TOXIC CHEMICAL

yABSORPTION the dose uptake in to the body

y DISTRIBUTION movement within the body

y METABOLISM/BIOTRANSFORMATION conversionto non toxic or toxic species

y E XCRETION removal from the body


3/34

Important aspects of ADME

processes includey Amount and time a chemical stays at the site of absorption

y Rate of absorption and amount absorbedamount absorbed

y Distribution of the chemical throughout the bodyy Speed of biotransformation and nature of metabolites

formed

y Whether a chemical can pass thru the cell membrane

y Whether a chemical or its metabolites are stored in thebody

y Rate of excretion if a chemical is administered faster thanit is excreted, it will accumulated in the body.


4/34

absorptiony Process whereby chemicals cross the body membrane

and enter bloods

y

Absorption is the first step in toxicokinetics of achemical. If a toxic substances is not absorbed itsconsidered not a health hazard

y Skin, lung s and GIT may considered as barriersseparating higher organisms from the environment

containing chemicalsy Chemicals must cross this barriers to exert adverse

health effect on the body and then pass thru variouscell membranes


5/34

y Enviroment

y Cell membranes of skin, lungs and GIT

y Blood capillary membrane

y Membranes cells within a tissue organ

y Membranes organelle: mitochondria, nuclues

y Some chemicals may cross cell membranes easily but some dont


6/34

Mechanism of crossing barriers1. Simple diffusion

y The term simple diffusion refers to a process whereby a

substance passes through a membrane without the aid ofan intermediary such as a integral membrane protein.

y The force that drives the substance from one side of themembrane to the other is the force of diffusion

y In order for substances to pass through a cell membrane by

simple diffusion it must penetrate the hydrophobic core ofthe phospholipid bilayer.

y The types of molecules that can do this are themselvessubstantially hydrophobic in nature such as carbondioxide, oxygen orethanol.


7/34

Simple diffusion

y In the figure the green triangleindicates a concentrationgradient of carbon dioxide. Theblue arrow indicates the

direction of net flow of carbondioxide. The carbon dioxidepenetrates the phospholipidbilayer without the aid of anintermediary molecule. Youshould be aware that the relative

sizes of the molecules in thisfigure are not correct. Thecarbon dioxide molecules aremuch smaller than thephospholipids.


8/34

Mechanism of crossing barriers2. Facilitated diffusion

This process does not

require ATP but doesrequire cell membraneproteins which are calledcarrier proteins to carrythe molecules across the

cell membrane from anarea of higherconcentration to an areaof lower concentration


9/34

Mechanisms of crossing barriers3. Active Transport

y Active Transport requires

the cell to use energy,usually in the form of ATP.

y Active Transport creates acharge gradient in the cellmembrane. For example inthe mitochondrion,

hydrogen ion pumps pumphydrogen ions into theintermembrane space ofthe organelle as part ofmaking ATP.


10/34

Mechanisms of crossing barriers

y Active Transport keepsunwanted ions or othermolecules out of the cell thatare able to diffuse throughthe cell membrane.

y Active transport uses energyto sendsubstances against thedirection they would travel bysimple diffusion: that is froma region of low concentrationto a region of highconcentration.


11/34


12/34

Mechanisms of crossing barriers

y Exocytosis (Exo (exit)

cytosis (cell) ) is a processin which a substance isexited from the cellwithout passing throughthe cell membrane.

y Examples of thigs thatmigh be exited includesecretion of proteins likeenzymes, hormones andantibodies.


13/34


14/34

Others factors affecting absorptiony Route of exposures - chemical maybe highly absorbed

from one route of exposure but nor from another

yTemperature - increased temperature aids absorptionthru skin

y Surface active material facilitate penetration

y Intergrity of the absorbing surface


15/34

Routes of exposurey Before chemicals can exert a toxic effect, it must come

in contact with a body surface

yThe route of exposure is the first body tissue achemical comes into contact where it maybe absorbed


16/34

Major routes areyy Mucosa of the GIT ingestionMucosa of the GIT ingestion

yy Mucosa of the respiratory tract inhalationMucosa of the respiratory tract inhalation

yyContact with the skin topical.Contact with the skin topical.

yy Contact with the eyeContact with the eye

y The probablity of adverse effect occuring depend on;

yy MagnitudeMagnitudeyy Duration, andDuration, and

y Frequency of exposure


17/34

1. ORAL GIT


18/34

1. Oral Exposure (GIT)yAn important route by which chemicals enter into

body

y

Some environmental chemicals enter the food chainy The main route for therapeutic drugs

y Suicide attempts

yy To enter the body via the GIT, chemicals must passTo enter the body via the GIT, chemicals must pass

through the GIT lining and capillary membranes beforethrough the GIT lining and capillary membranes beforeentering the bloodentering the blood

yAbsorption can happen along the GIT however degreeof absorption depends on the chemicals


19/34

a) Mouth and esophagusa) Mouth and esophagus

yy Little absorption occurs due to the short time the chemicalLittle absorption occurs due to the short time the chemicalremains there, exceptions include nitroglycerin.remains there, exceptions include nitroglycerin.

b) Stomachb) Stomach

yy Stomach content is acidic and weak organic alcoholStomach content is acidic and weak organic alcohol

yy The acid might break some chemicals downThe acid might break some chemicals down

yy Some drugs can be absorbed in the stomachSome drugs can be absorbed in the stomach egeg; Aspirin is a; Aspirin is alipid soluble and enter circulation by crossing the gastriclipid soluble and enter circulation by crossing the gastricmucosamucosa


20/34

C) Small intestine

y Absorption of alkaline chemicals (and food) is greatest

here. Soluble molecules absorbed by diffusiony Carrier mediated mechanisms exist here for some larger

particles

D) ColonLittle absorption takes place here.


21/34

Fate of the chemical absorbed thru

GITy Most chemicals are absorbed in the GIT by simple

diffusion therefore lipid soluble substances are rapidly

y All blood leaving the absorptive surfaces of the GIT flows

directly to the liver through the portal bloody The liver can alter a chemical (detoxify it or increase its

toxicity)

y Chemicals converted to a more toxic form in the liver show

greater toxicity if ingested than if absorbed through skinor lung.

y Chemicals that are detoxified in the liver are less toxicwhen administered orally than when absorbed across theskin or lung.


22/34

Absorption through Skiny Skin comes into contact with many toxic chemicals

(caustics and corrosives)

y Skin consists of many layers and forms a barrier to the

absorption of many chemicals, but some chemicals canpass through skin.

y Cells in the outer layer of the skin are resistant tochemicals, also there are no blood vessels in the outer layer.

y

If a chemical manages to pass through the outer layer itreadily passes through the rest of the skin and enters thecirculation.

y Skin contact occurs in the occupational situation and inthe home


23/34

Factors influencing absorption of

chemicals through the skin:y Period of time skin is exposed and the concentration.

y Integrity of the skin

y Formulation of the chemical and its chemistryy Skin is relatively impermeable to aqueous solutions.

y Skin is permeable in varying degrees to lipophilicchemicals

y Detergents increase penetration of solutes through theskin.


24/34

Inhalation of chemicalsy Important route for absorption of chemicals in the

environment, absorption mostly occurs in the alveoli

of the lungsy Chemicals absorbed by the lungs are usually;

y Gases

y Vapours of volatile liquids

y Aerosolsy Particles


25/34

Factors affecting toxicity of

chemicals in the atmospherey Physical properties of the chemical

y lipid- soluble chemicals penetrate the alveoli more effectively

.They are distributed throughout the body than water- solubleone and cross cell membranes easily

y Penetration and distribution of fibres and particles in therespirotary tract are mainly determined by their size.

y Large particles are deposited in the nose little absorption

y

Small particles penetrate to the alveoli and can be absorbedy Some particles remain in the alveoli indefinitely (for

example, Coal dust and asbestos fibres lead to disease (e.gasbestosis)


26/34

Conty Concentration of the chemical.

y The period of time over which the chemical is inhaled.

y Chemicals may cause chronic bronchitis breakdown ofthe alveolar walls and lung cancer e.g. cigarette smoke.


27/34

4. EYEy Local and systemic effects can be produced by

chemicals in the atmosphere via absorption at the eye

y

Systemically active amounts of a chemical may beabsorbed from blood vessels in the eye and /or nasalmucosa following passage down the nasolachrymalduct.


28/34

DISTRIBUTIONy The way a chemical moves from the site of absorption

to other parts of the body

y

When a chemical is absorbed, it passes into theinterstitial f luid and then into local cells or thebloodstream.

y Once in blood, chemicals circulate either free or

bound to a plasma protein or blood cellsy The chemical then passes through the capillary

membrane and cell membranes of the target organ(only the free form)


29/34


30/34

Factors affecting distribution1. Route of exposures

2. The amount of blood flowing thru the tissue

3. The presence f the structural barrier4. Storage of chemical in tissue


31/34

1. Route of exposurey Biotransformation, storage and excretion are

influenced by the path a chemical takes through the

body and the time involvedy Chemicals absorbed through the GIT are carried

directly to the liver, then to the heart, the lungs then toother organs

y

Chemicals absorbed through the skin or lungs enterthe blood, then go to the heart and then aredistributed to various organs before they reach theliver


32/34

2. The amount of blood flowing the

tissuey Rate of distribution of a chemical to an organ is

determined by blood flow and rate off diffusion from

capillaries into the cellsy The final distribution is influenced by the

y affinity of the chemical for various tissues,,

y e..g.. adipose tissue accumulates lipid-solluble

y chemicals, even though it does not have ay high blood flow.


33/34


34/34

4.Storage of chemicals in tissuesy Main sites for storage of chemicals within the body are:

a) Plasma proteins.y Plasma proteins bind foreign and body chemicals the extent

of binding varies between chemicals. Binding is reversible.

b) Adipose tissue (fat)y Lipid-soluble chemicals may be deposited in fat.

c)Boney During bone formation, calcium and hydroxyl ions are

incorporated in the bone, several chemicals may be substituted

d) Liver and kidneys.y These organs have a high capacity to bind many chemicals.

TOXICOKINETICS 1

Documents

Transcript of TOXICOKINETICS 1