ENVIRONMENTAL TOXICOLOGY Chapter 4 Toxicokinetics Mohd Amir Bin Arshad
Toxicokinetics study on how a substance gets into the body and what happens to it in the body"
The kinetics (movement) of substances through the body known as: Toxicokinetics for non-drug chemicals (environmental and occupational chemicals) Pharmacokinetics for drugs.
Factors afecting an individual s response The dose Uptake into the body (absorption) Movement within the body (distribution) Conversion to toxic or non-toxic species (biotransformation) Removal from the body (excretion).
Time-dependent process of toxicokinetics. Absorption Distribution Biotransformation Elimination 1 st 2 nd 3 rd 4 th Storage
Important aspects of ADME processes: Amount of and time a chemical stays at the site of absorption. Rate of absorption and amount absorbed. Distribution of the chemical throughout the body. Speed of biotransformation and nature of the metabolites formed.
Whether a chemical can pass through cel membranes. Whether a chemical, or its metabolites are stored in the body. Rate of excretion if a chemical is administered faster than it is excreted, it wil accumulate in the body.
Routes of Exposure There are several exposure routes: Ingestion - Oral (mouth) Dermal (through the skin) Inhalation (breathing) Injection (subcutaneous, intravenous, intramuscular)
Absorption Distribution Storage Biotransformation Elimination Toxicokinetics Process How toxicants enter the organism How toxicants travel within the organism How some tissues preferentialy harbor a toxicant How toxicants are altered by chemical changes in organism How toxicants are removed from organism
The disposition of c hemic als entering the body (from C.D. Klaassen, Casarett and Doul s Toxic ology, 5th ed., New York: Mc Graw-Hil, 1996).
1 st Absorption Process whereby chemicals cross body membranes and enter blood. Absorption is the first step in the toxicokinetics of a chemical. If a toxic substance is not absorbed, it is not a health hazard.
Skin, lungs and GIT may be considered as barriers separating higher organisms from the environment containing chemicals. Chemicals must cross one of these barriers to exert an adverse efect on the body and then pass through various cel membranes.
For a xenobiotic to enter the body (as wel as move within, and leave the body) it must pass across cel membranes (cel wals). Cels in solid tissues (such as skin or mucous membranes of the lung or intestine) are so tightly compacted that substances can not pass between cel membranes. Xenobiotic have the ability to penetrate cel membranes and cross several membranes in order to go from one area of the body to another.
Mechanisms of Absorption may occur by: 1. Simple difusion (most common). 2. Facilitated difusion 3. Active transport 4. Endocytosis (Pinocytosis and phagocytosis)
PASSIVE TRANSPORTATION
FACILITATED DIfUSION
ACTIVE TRANSPORTATION
ENDOCYTOSIS (Phagocytosis and Pinocytosis)
In general, the greater the amount of the chemical in contact with the absorbing surface, the greater the amount of the dose that is absorbed.
Factors afecting absorption 1.Routes of exposure. 2.Concentration of the substance at the site of contact. 3.Chemical and physical properties of the substances. 4.Temperature - increased temperature aids absorption through the skin.
Routes Of Exposure Before a chemical can exert a toxic efect, it must come in contact with a body surface. The route of exposure is the first body tissue a chemical comes into contact with and from where it may be absorbed.
The primary routes of exposure
Oral exposure (GIT) An important route by which chemicals enter the body. The main route for the intake of many therapeutic drugs. Suicide attempts often involve an overdose ingested chemical.
Children may ingest toxic chemicals. To enter the body via the GIT, chemicals must pass through the GIT lining and capilary membranes before entering the blood.
(a) Mouth and oesophagus Little absorption occurs due to the short time the chemical remains there. (b) Stomach Stomach contents are acidic and weak organic acids are absorbed The acid may break some chemicals down. Some drugs can be absorbed in the stomach, e.g. Alcohol.
(c) Smal intestine Absorption of alkaline chemicals (and food) is greatest here. Soluble molecules are absorbed by difusion. (d) Colon and rectum Little absorption takes place here.
Chemical Fate of absorbed through the GIT Most chemicals are absorbed in the GIT by simple difusion, therefore lipid-soluble substances are rapidly absorbed. Al blood leaving the absorptive surfaces of the GIT flows directly to the liver through the portal blood vessels. The liver can alter a chemical (detoxify it or increase its toxicity).
Chemicals converted to a more toxic form in the liver show greater toxicity if ingested than if absorbed through skin or lung. Chemicals that are detoxified in the liver are less toxic when administered oraly than when absorbed across the skin or lung.
Absorption through the skin Skin comes into contact with many toxic chemicals (corrosives). Skin consists of many layers and forms a barrier to the absorption of many chemicals, but some chemicals can pass through skin. Cels in the outer layer of the skin are resistant to chemicals, also there are no blood vessels in the outer layer.
If a chemical manages to pass through the outer layer, it readily passes through the rest of the skin and enters the circulation. Skin contact occurs in the occupational situation and in the home.
Factors influencing absorption of chemicals through the skin: Period of time skin is exposed and the concentration. Integrity of the skin. Formulation of the chemical and its chemistry. Skin is relatively impermeable to aqueous solutions.
Skin is permeable in varying degrees to lipophilic chemicals. Detergents increase penetration of solutes through the skin.
Inhalation of chemicals Important route for absorption of chemicals in the environment, absorption mostly occurs in the alveoli of the lungs. Chemicals absorbed by the lungs are usualy: Gases Vapours of volatile liquids Aerosols Particles
Factors affecting toxicity of chemicals in the Atmosphere Physical properties of the chemical. - Lipid-soluble chemicals penetrate the alveoli more effectively than water-soluble ones. They are distributed throughout the body and cross cell membranes easily.
- Penetration and distribution of fibres and particles in the respiratory tract are mainly determined by their size. * Large particles are deposited in the nose - little absorption. * Small particles penetrate to the alveoli and can be absorbed. * Some particles remain in the alveoli. For example, coal dust and asbestos fibres lead to disease (e.g. asbestosis).
Concentration of the chemical. The period of time over which the chemical is inhaled. Chemicals may cause chronic bronchitis, breakdown of the alveolar walls and lung cancer e.g. cigarette smoke.
Eye Local and systemic effects can be produced by chemicals in the atmosphere via absorption at the eye. Systemically active amounts of a chemical may be absorbed from blood vessels in the eye and /or nasal mucosa following passage down the nasolachrymall duct.
BIODISTRIBUTION The way a chemical moves from the site of absorption to other parts of the body. When a chemical is absorbed, it passes into the interstitial fluid and then into local cells or the bloodstream. Once in blood, chemicals circulate either free or bound to a plasma protein or blood cells. The chemical then passes through the capillary membrane and cell membranes of the target organ.
Thus, once a chemical is in the blood stream, it may be: Excreted. Stored. Bio-transformed. The chemical or its metabolites may interact with cell components. The concentration of a chemical in the blood thus depends on the site of absorption and the rate of biotransformation and excretion.
Factors affecting the bio-distribution of a chemical 1. Route of exposure 2. The amount of blood flowing through the tissue. 3. The presence of structural barriers 4. Storage of chemicals in tissues
(1) Route of exposure Biotransformation, storage and excretion are influenced by the path a chemical takes through the body and the time involved. Chemicals absorbed through the GIT are carried directly to the liver, then to the heart, the lungs then to other organs. Chemicals absorbed through the skin or lungs enter the blood, then go to the heart and then are distributed to various organs before they reach the liver.
(2) The amount of blood flowing through the tissue. Rate of distribution of a chemical to an organ is determined by blood flow and rate of diffusion from capillaries into the cells. The final distribution is influenced by the affinity of the chemical for various tissues, e.g. adipose tissue accumulates lipid-soluble chemicals, even though it does not have a high blood flow.
(3) Presence of structural barriers Barriers Blood-brain barrier Placental barrier Blood-testis barrier Description Many toxic chemicals are prevented from entering the brain by a barrier consisting of special cells between the capillary endothelium and nerve cells. The placenta transports nutrients from the mother to the fetus and wastes from the fetus to the mother. The placenta protects the developing fetus from many chemicals in the maternal circulation. Protects the developing sperm from some chemicals
(4) Storage of chemicals in tissues Storage Plasma proteins Adipose tissue (fat) Bone Liver and kidneys Description Plasma proteins bind foreign and body chemicals the extent of binding varies between chemicals. Binding is reversible. Lipid-soluble chemicals may be deposited in fat. During bone formation, calcium and hydroxyl ions are incorporated into bone, several chemicals may be substituted. These organs have a high capacity to bind many chemicals.
BIOTRANSFORMATION The process by which a substance is changed from one chemical form to another by a chemical reaction within the body. Also referred to as metabolism Biotransformation of a foreign chemical can be either beneficial or harmful.
EXCRETION Excretion is a major determinant of the potential toxicity of a foreign chemical, rapid excretion less toxicity. Chemicals must pass through membranes to leave the body. Chemicals may be excreted as the parent compound or metabolites formed as a result of metabolism.
(1) Urine via the renal system The kidney is a major route of excretion and it functions to excrete body wastes and toxic chemicals. Many chemicals have to be bio-transformed to more water-soluble products before they can be excreted in the urine. Kidney damage (chemicals, infections, age) reduced excretion-----------toxicity.
1. Glomerular filtration Processes of excretion Blood is filtered at the beginning of the renal tubule. The filtration membrane contains large pores so small molecules readily pass into the tubule. About 99% of the filtrate is reabsorbed into blood, the remaining 1% is excreted as urine. Proteins and blood cells are too large to pass through the pores. 2. Tubular secretion 3. Tubular reabsorption Some substances are actively transported from the blood into the renal tubule and are thus also excreted in the urine. Active------ From tubules into blood capillaries.
(2) Faeces - via the GIT Second most important route for elimination of foreign chemicals. Indigestible material, varying amounts of nutrients and foreign chemicals pass through the GIT unabsorbed. Absorption depends on chemistry - lipid-soluble substances are well absorbed.
Excretion of toxic chemicals in faeces occurs by 2 processes (a) Excretion by the liver into bile The liver produces bile for export to the intestine. Bile is a route for excretion of foreign chemicals and their metabolites. The liver can remove a chemical from blood after absorption from the GIT before it reaches the general circulation for distribution to other parts of the body.
Once a chemical in bile enters the intestine, it can either be reabsorbed or excreted with faeces. Liver disease can cause a decreased flow of bile and hence affect the efficiency of excretion by this route. (b) Direct excretion into the lumen of the GIT. Minor route of excretion, however chemicals can be directly transferred from blood into the intestine and excreted via faeces.
(3) Exhaled air - via the respiratory system The lungs are an important route for excretion of foreign chemicals and metabolites that exist as gases in blood. Gases and volatile liquids dissolved in blood diffuse from blood into alveoli down a concentration gradient and are expired. Exhalation is different to most other routes of excretion in that lipid-soluble substances are efficiently excreted across the alveolar membranes.
Other routes of excretion Breast milk Sweat, saliva, tears and semen. Toxic chemicals may pass in milk to the suckling infant during lactation (e.g. DDT and lead). Chemicals can be passed from cows to humans via diary products. The amount of a chemical excreted in sweat, hair, nails and saliva is very smal but may be important in forensic analysis or for industrial diagnosis of exposure.
Summary The probability of adverse effects occurring in response to chemical exposure depends on: The magnitude, frequency, duration and route of exposure. These factors determine the amount of chemical to which the body is exposed and hence the amount absorbed.
The amount absorbed determines the amount of the chemical available for distribution throughout the body. If repeated exposures occur, the amount of the parent chemical and biotransformation products. e.g. if detoxification is slow, repeated exposures may lead to accumulation of toxic chemicals.
Opposing absorption and metabolite accumulation is excretion. Thus, for a particular exposure, the probability of a toxic effect being induced and its magnitude depends on: The rate of absorption. Metabolism (activation and detoxification). Excretion of the parent chemical and its metabolites.
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