toxic o dynamics

8/12/2019 Toxic o Dynamics

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Toxicodynamics

Toxicodynamics refers to the actions and interactionsof toxicants within the organism

It describes the processes at organ, tissue, cellular

and molecular levels

Toxicity of toxicants is usually due to an interaction withsome cellular constituents that ultimately affects certain

functions These interactions can results into either cellular

dysfunction or destruction.


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Molecular mechanisms of toxicity

Virtually all biomolecules are potential targets fortoxicants

Toxicants can react with its target molecule in differentways;

non-covalent, reversible binding;

covalent irreversible interactions;

incorporation into endogenous compounds.


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Non -covalent, reversible bindin g to recepto rs Many toxicants act through binding to a receptor molecule. This can activate or

inactivate membrane receptors, intracellular receptors, ion channels or enzymes Thus, triggering a series of changes seen as the toxic effects.

Covalent b inding : irreversib le interact ions with receptors

Some toxicants binds irreversibly to their targets In most cases the toxicant has to be converted to a reactive intermediate by

bioactivation, before it can bind covalently to a receptor Covalent binding can occur with different molecules, producing different effects

DNA Many toxicants that are carcinogenic do so by covalent interaction with

nucleophilic groups on DNA bases.

The DNA adducts thus generated may cause mutations leading to cancer if theyoccur at certain critical positions. In other positions, the DNA adducts may lead tocell death.


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Proteins Reactive metabolites of toxicants may bind non-specifically to

thiol or amine groups of proteins.

This may result in loss of function of the protein be it enzyme, carrierprotein, structural protein etc.

if sufficient protein molecules are incapacitated, the cell may losecontrol and die by apoptosis or necrosis.

This is not a problem when the cell can be replaced byregeneration (e.g. liver). However, if the loss occurs in cells that can not easily be replaced as

in the CNS, may cause loss of function of the organism.

Low molecu lar weight compoundsIn most cases this may result in exhaustion of the particularcompound, e.g. glutathione


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Cellular dysfunction

Once the chemical has changed some molecular processes inside the cell,the response of the cell or organism will depend on the nature of thechange. The response may be;

Decreased synthesis of a certain essential protein. In which case, thecell itself may show little damage.

The toxicity may be expressed elsewhere, due to lack of a particularprotein or a highly specialized function of the cell may be affected

selectively, i.e. production of a hormone or an essential metabolite.

Modification of signal transmission in the nerve or neuronal cells, dueto direct toxic effect of a chemical via receptors or ion channels.

In most cases, the primary effect will have consequences for the cellsurvival. This is true for those compounds that affect energyproduction or membrane carriers involved in ion homeostasis


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Impaired cellular homeostasis

This is the most severe final condition that ultimatelyleads to cell death. Cells contain a dedicated set of enzymes and processes

that regulate various kinds of intracellular parameters i.e.ion concentrations, ATP/ADP ratio, redox potential,mitochondrial, cell membrane potential and DNA integrity.

When toxicants binds to any of the proteins thatregulate one of these control systems, homeostasisbecome affected, this may result to several changes

most of which are deleterious to the cells and theorganism.

These include;


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In the presense of several metal ions, i.e. ferrous ions, the

superoxide can be converted to even more reactive hydroxylradical.

(iii) H2O2+ Fe

2+

= HO.+ OH + Fe

3+

Due to their radical character, ROS are the cause of several forms oftoxicity. Under conditions of severe ROS production, the clearance ofROS may fail because one of the components becomes rate limitingleading to expression of toxicity.

When lipids are the target, then the lipid peroxidation may occur. Theoxygen radical leads to a series of self-propagating radical reactions,as a result the fatty acids themselves turn into radicals. Ultimatelythe lipids are destroyed

The presense of vitamin E and Vitamin C (Endogenousantioxidants) in the membrane can stop the propagation ofthe radical chain reactions, but vitamin E may becomedepleted during massive peroxidation.


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Sustained rise in intracel lular calc ium

Calcium is crucial for the regulation of large number ofproteins, - its concentration is tightly controlled

Interference of toxicants with this control system can lead toimpairment of the ability to maintain structural and functinalintegrity

The fact that many proteins and enzymes are tightly

regulated by free intracellular calcium contributes tothese effects

Impaired ATP synthesis

Binding of toxicants to DNA can lead to mutations andultimately to uncontrolled proliferation of cells, i.e. cancer.

When the damage is too extensive, the repair capacity isinsufficient.


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DNA damage

Binding of toxicants to DNA can lead to mutations andultimately to uncontrolled proliferation of cells, i.e. cancer.

When the damage is too extensive, the repair capacity isinsufficient

Cell destructionThis can be in two forms; necrosis and apoptosis

In necrosis, cells swell, rupture and release their contentsinto the body, a process accompanied by inflammation

But cells can also die through cell suicide, a process calledapoptosis. During apoptosis, the cell initiates a geneticprogramme leading to its own death; basically it is aphysiological process


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Within a population, the majority of responses to a toxicant are similar;however, a wide variance of responses may be encountered, someindividuals are susceptible and others resistant. A graph of the individualresponses can be depicted as a bell-shaped standard distribution curve.

The dose-response curve normally takes the form of a sigmoid

curve.

For most effects, small doses are not toxic. The point at which toxicity first appears is

known as the thresholddose level.

From that point, the curve increases with higher dose levels.

In the hypothetical curve ; no toxicity occurs at 5 mg whereas at 35 mg 100% of

the individuals experience toxic effects.

A threshold for toxic effects occurs at the point where the body's

ability to detoxify a toxicant or repair toxic injury has beenexceeded.

For most organs there is a reserve capacity so that loss of some organ

function does not cause decreased performance.

For example, the development of cirrhosis in the liver may not result in a

clinical effect until over 50% of the liver has been replaced by fibrous tissue.


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Knowledge of the shape and slope of the dose-

response curve is extremely important in

predicting the toxicity of a substance at specificdose levels.

Major differences among toxicants may exist notonly in the point at which the threshold is

reached but also in the percent of population

responding per unit change in dose (i.e., the

slope).


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Factors affecting toxicity of toxicants

Toxicants cause many types of toxicity by a variety ofmechanisms. Some chemicals are themselves toxic.

Others must be biotransformed before they cause toxicity.

Many toxicants distribute in the body and often affect onlyspecific target organs.

- Others, however, can damage any cell or tissue that they contact.

- The target organs that are affected may vary depending on dosage

and route of exposure- For example, the target for a chemical after acute exposure may be

the nervous system, but after chronic exposure the liver.


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1. Form or ph ys ical state

The form of a substance may have a profound impact on itstoxicity especially for metallic elements. For example;

the toxicity of mercury vapor differs greatly from methyl mercury.

chromium; Cr3+ is relatively nontoxic whereas Cr6+ causes skin or

nasal corrosion and lung cancer.

2. Chem ical activity

The innate chemical activity of substances also variesgreatly. Some can quickly damage cells causing immediate celldeath. Others slowly interfere only with a cell's function. For

example; hydrogen cyanide binds to cytochrome oxidase resulting in cellular

hypoxia and rapid death

nicotine binds to cholinergic receptors in the CNS altering nerve

conduction and inducing gradual onset of paralysis


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3. Dosage

The dosage is the most important and critical factor in determining if asubstance will be an acute or a chronic toxicant.

Virtually all chemicals can be acute toxicants if sufficiently large doses areadministered.

Often the toxic mechanisms and target organs are different for acute and

chronic toxicity.

4. Route of expo su re Exposure route is important in determining toxicity. Some chemicals

may be highly toxic by one route but not by others. Two major reasonsare; differences in absorption and distribution within the body.

Frequently there are different target organs for different routes of

exposure. For example: ingested chemicals, when absorbed from the intestine, distribute first to the

liver and may be immediately detoxified

inhaled toxicants immediately enter the general blood circulation and can

distribute throughout the body prior to being detoxified by the liver


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5. Species

Toxic responses can vary substantially depending on the species.

Most species differences are attributable to differences in metabolism.

Others may be due to anatomical or physiological differences.

Selective toxicity refers to species differences in toxicity between

two species simultaneously exposed.

This is the basis for the effectiveness of pesticides and

drugs. Examples are: an insecticide is lethal to insects but relatively nontoxic to animals

antibiotics are selectively toxic to microorganisms while virtually nontoxic

animals


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6. Age

Age may be important in determining the response to toxicants. Somechemicals are more toxic to infants or the elderly than to youngadults. For example: -

parathion is more toxic to young animals

nitrosamines are more carcinogenic to newborn or young animals

7. Sex

Although uncommon, toxic responses can vary depending on sex. male rats are 10 times more sensitive than females to liver damage from

DDT

female rats are twice as sensitive to parathion as male rats

8. Ab i l ity to be absorbed The ability to be absorbed is essential for systemic toxicity to

occur. Some chemicals are readily absorbed and others poorlyabsorbed.

For example, nearly all alcohols are readily absorbed when ingested,

whereas there is virtually no absorption for most polymers.


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9. Metabo lism

Metabolism, also known as biotransformation, is a major factor indetermining toxicity.

10. Distr i bu tion

The distr ibut ion of toxicants and toxic metabolites throughoutthe body ultimately determines the sites where toxicityoccurs. Blood serves as the main avenue for distribution. A majordeterminant of whether or not a toxicant will damage cells is itslipid solubility. Many toxicants are stored in the body.

11. Excretion

The site and rate of excretionis another major factor affecting thetoxicity of a xenobiotic. The kidney is the primary excretoryorgan, followed by the gastrointestinal tract, and the lungs (forgases). Impaired kidney function causes slower elimination oftoxicants and increases their toxic potential.


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Interactions Humans are normally exposed to several chemicals at one time rather

than to an individual chemical. Medical treatment and environment

exposure generally consists of multiple exposures. Examples are:

hospital patients on the average receive 6 drugs daily

home influenza treatment consists of aspirin, antihistamines, and

cough syrup taken simultaneously

drinking water may contain small amounts of pesticides, heavymetals, solvents, and other organic chemicals

gasoline vapor at service stations is a mixture of 40-50 chemicals

Toxicants administered or received simultaneously may act

independently of each other. However, in many cases, the presence ofone chemical may drastically affect the response to anotherchemical. The toxicity of a combination of chemicals may be less or itmay be more than would be predicted from the known effects of eachindividual chemical. The effect that one chemical has on the toxic effect

of another chemical is known as an interaction.


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Types of Interactions There are four basic types of interactions. Each is based on the expected

effects caused by the individual chemicals.

Addi t iv i ty

Occurs when the response resulting from combined exposure to two ormore chemicals is the sum of the expected individual responses.

Itis the most common type of drug interaction.

Examples of chemical or drug additivity reactions are: Two central nervous system (CNS) depressants taken at the same time, a

tranquilizer and alcohol, often cause depression equal to the sum of that

caused by each drug

Organophosphate insecticides interfere with nerve conduction. The toxicity of

the combination of two organophosphate insecticides is equal to the sum of

the toxicity of each

Chlorinated insecticides and halogenated solvents both produce liver

toxicity. The hepatotoxicity of an insecticide formulation containing both is

equivalent to the sum of the hepatotoxicity of each.


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Antagon ism

Exposure to one chemical result in a reduction in the effect of the otherchemical.

This is often a desirable effect in toxicology and is the basis for mostantidotes. Examples include;

Severe drop in blood pressure resulting from a barbiturate overdose can be

reversed by administration of a vasopressor to increase blood pressure.

Mercury toxicity can be reduced by chelating the mercury ions with

dimercaprol

Swallowed poison can be adsorbed by activated charcoal to reduce the rate ofabsorption

Carbon monoxide poisoning is treated with oxygen which displaces the

carbon monoxide from haemoglobin receptors

Potentiat ion Exposure to one chemical results in the other chemical producing an

effect greater than if given alone.

In most cases potentiationoccurs when a chemical that does not have aspecific toxic effect makes another chemical more toxic.


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Examples are:

The hepatotoxicity of carbon tetrachloride is greatly enhanced by thepresence of isopropanol. Such exposure may occur in the workplace.

Drugs which compete for binding sites on albumin increase the level of

free warfarin to 4% causing fatal hemorrhage.

Synergism

Exposure to one chemical causes a dramatic increase in the effect of

another chemical. Synergismcan have serious health effects. With synergism, exposure

to a chemical may drastically increase the effect of another chemical.

Examples are:

The combination of exposure to asbestos and cigarette smoke results in

a significantly greater risk for lung cancer than the sum of the risks ofeach.

The hepatotoxicity of a combination of ethanol and carbon tetrachlorideis much greater than the sum of the hepatotoxicity of each.

toxic o dynamics

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