What is Toxicology?

It is the study of the adverse effects of chemical or physical

agents on living organisms.

It is one of the multidisciplinary fields of science which encompasses

many sciences such as basic biochemical, chemical, pathological and
physiological knowledge along with experimental observation to gain an
understanding of why certain substances cause the disruption in a biological
system which may lead to toxic effects.
Scope of Toxicology

Descriptive toxicology
• It evaluates the toxicity of chemicals exposed to human beings and environment as a
whole via gathering information from animal experimentation

Mechanistic toxicology
• It focuses on the study of mechanisms by which chemicals or physical agents exert
their toxicity on living organisms

Clinical toxicology
• It is concerned with the diagnosis & management of poisoned patients
Scope of Toxicology

enviromental toxicology
• It focuses on the effects of chemical or physical pollutants in the environment on
living organisms. It deals with pollution & industrial hygiene.

Genetic toxicology
• It is a branch of the field of toxicology that assesses the effects of chemical and physical
agents on the hereditary material (DNA) of living cells.

Forensic toxicology
• It is concerned with identification of the cause of death and determining its
circumstances in a postmortem investigation
What is a Poison?

All substances are poisons;

there is none that is not a poison.
The right dose
differentiates a poison and a remedy.
"The dose makes the poison.“

Paracelsus (1493-1541)
Toxicologic terms
Toxin:
These are naturally produced toxic substances such as snake venom.

Toxicant:
Human-made toxic substance such as industrial wastes.

Xenobiotic
A chemical which is foreign to the normal physiology of the body.
It includes drugs and other chemicals such as pesticides
Types of toxic agents: Source
1) Therapeutic agents
Drug toxicity can be due to over doses, frequent administrations of
therapeutic doses & drug interactions (Digoxin & Paracetamol).

2) Industrial Chemicals
These chemicals may contribute to environmental pollution & they may be a
direct hazard in the work place they are used (Heavy metals).

3) House-hold chemicals
The top household products ingested are cleaning agents, cosmetics &
personal products.
Types of toxic agents: Source
4) Environmental contaminants
Main sources of pollution to the environment are industrial processes, pesticides &
smokes from factories & vehicles. Environmental pollutants may be released into
the air, water, or dumped onto land.
5) Natural Toxins
Many plants & animals produce toxic substances for both defense & offensive
purposes. Natural toxins may feature in poisoning via containing in food, by
accidental ingestions of poisonous plants or animals & by stinging & biting.
6) Drugs of abuse
Excessive or improper use of drugs or other substances for non-medical purposes,
usually for altering consciousness known as abuse of drug. There are a lot of drugs of
abuse with high potential of dependence (e.g alcohol, morphine, nicotine…).
Routes of Toxic Exposure
Ingestion Inhalation
• - Common agents: Household products,
•Common agents: Toxic gases, fumes,
Cleaning agents, Drugs, plants, or foods
Carbon monoxide, ammonia, chlorine
• Absorption occurs in the stomach and
•Absorption occurs via the capillary—
small intestine.
alveolar membrane in the lungs.

Surface Absorption Injection

•Common agents: Insecticides as •Common agents: Animal bites &
Organophosphates Intentional injection of drugs of abuse
•Absorption occurs through capillaries •Substance enters directly into the
in the skin. body through a break in the skin.
Classification of toxicity
1-According to circumstances of toxicity

Accidental Deliberate self

Toxicity (non- Toxicity (Suicidal
intentional) or criminal)
Occur by mistakes and Occur when a
usually happen to person attempts to
children (below 5- kill himself or
years old) another person.
e.g.:With aspirin, iron e.g: with cyanide,
preparations, pesticides, barbiturates,
kerosene…..etc. salicylates…..etc.
Classification of toxicity
2- According to incidence of toxicity

Home Occupational

This includes
Which occurs in or industrial and
around home. agricultural
E.g: potassium poisoning.
hydroxide, E.g.: inhalation of
disinfectants pesticides.
Classification of toxicity
3- According to onest of toxicity

Acute Sub-acute Sub-chronic Chronic

toxicity toxicity toxicity toxicity
Results from a Results from either
single exposure to It results from repeated or continuous
poison (<24h) It results repeated exposures over a long
from exposure for period of time (>3
The toxic effect repeated several weeks or months)
will appear shortly months.
after exposure e.g. exposue
within few minutes to toxic (1-3 months) Chronic toxicity may be
to one day agent for E.x: Workplace due to accumulation of
following the weeks exposure to lead injury rather than
exposure. (<1 over a period of accumulation of
several weeks chemicals
Ex: asphyxiation month)
can result in
from exposure to a anemia.
high concentration Ex: Cirrhosis in alcoholics
of CO
Toxicological effects

- Immediate toxic effects: can be defined as those that occur or develop rapidly after
a single administration of a substance,

- Delaye toxic effects are those that occur after the lapse of some time.
Ex: Carcinogenic effects of chemicals usually have a long latency period, often 20 to
30 years after the initial exposure, before tumors are observed in humans. For
example, daughters of mothers who took diethylstilbestrol (DES) during pregnancy
have a greatly increased risk of developing vaginal cancer
Toxicological effects

- Some toxic effects of chemicals are reversible, and others are irreversible.

- If a chemical produces pathological injury to a tissue, the ability of that

tissue to regenerate largely determines whether the effect is reversible
or irreversible.
- Thus, for a tissue such as liver, which has a high ability to regenerate,
most injuries are reversible, whereas injury to the CNS is largely
irreversible because differentiated cells of the CNS cannot divide and be
replaced.

- Carcinogenic and teratogenic effects of chemicals,

once they occur, are usually considered irreversible toxic effects
Toxicological effects

- Local effects are those that occur at the site of first contact between the biological
system and the toxicant.
Such effects are produced by the ingestion of caustic substances or the inhalation of
irritant materials.
EX: chlorine gas reacts with lung tissue at the site of contact, causing damage and
swelling of the tissue,

Systemic effects require absorption and distribution of a toxicant from its entry
point to a distant site, at which deleterious effects are produced.

- For some materials, both effects can be demonstrated. For example, tetraethyl lead
produces effects on skin at the site of absorption and then is transported systemically
to produce its effects on the CNS and other organs.
Interactions of toxicants
Additive Synergistic Potentiation Antagonism
The combined Potentiation occurs
effect of two The combined when one substance
chemicals is effects of two does not have a toxic
equal to the effect on a certain Occurs when
chemicals are two
sum of the much greater organ or system but
effects of each when added to chemicals
than the sum administered
agent given of the effects another chemical
alone makes that chemical together
of each agent interfere with
(example: 1 + given alone much more toxic
1 = 2). (example:0 + 2 = 10). each other’s
(example: 1 + actions or
EX: the 1 = 3). Ex: Isopropanol is one interferes
effect of two Ex: CCl4 and not hepatotoxic, but with the
organophosp ethanol are when it is action of the
-hate hepatotoxic administered with other
insecticides show CCl4, the (example: 4 +
given synergestic hepatotoxicity of (-4) =0
together is effects CCl4 is much greater
usually than that when it is
additive. given alone.
Toxicokinetic (TK) processes

ABSORPTION DISTRIBUTION METABOLISM EXCRETION

EXTERNAL BLOOD PLASMA
PHASE-1 KIDNEYS
MEMBRANE
LIVER
BARRIERS
xenobiotic lungs
skin TISSUES PHASE-2 saliva
G.I. tract sweat
lungs depots breast milk
I) Absorption : GIT
 pH of the stomach & intestine:
• Weak acidic agents such as aspirin are highly absorbed from the
stomach

• Weak basic agents such as amphetamine are highly absorped from the
intestine
 Amount & type of food:
• Presence of food in stomach delays the absorption of poisons.
So, the toxicity is increased when the poison is taken on empty
stomach
• Type of the food will affect rate of absorption: Protein & fat
delay absorption
I) Absorption : Skin

Uptake of chemicals by the skin depends on:

• The general condition (abrasions, cuts, etc)
• The thickness (arms thin, palms thick)
• Application of corrosive acids or alkalis organic
solvents & which increase the skin`s permeability
• The nature of the absorption surface
- DDT is easily absorbed form the chitinous
exoskeleton of insect than mammalian`s skin
I) Absorption : Lung

Uptake of chemicals by the lung depends on:

- Small particles (< 1 μm) goes down in the alveoli and can
cause e.g. silicosis or asbestosisthe thickness

- Gas reactivity: very reactive gases (HCl, NH3, SO2) are irritating
and blocks respiration and can therefore not be inhaled in larger
quantitiesWhile Chemicals with intermediate reactivity
and lipophilicity(phosgene, ozone, isocyanates) can be inhaled
and give injuries at all levels in the lungs
II) Distribution

 Volume of distribution (Vd) is defined as the apparent volume into which asubstance
is distributed.
Vd = dose /plasma concentration
 The blood concentration of a toxicant depends on its volume of distribution (Vd)
- Small Vd = High concentration in plasma
Plasma
- Large Vd = low concentration in plasma (4 litres)
 The importance of volume of distribution in toxicology is
Interstitial Fluid
- Predicting peak blood concentration of the (10 litres)
chemical taken
Intracellular Fluid
- Deciding whether to apply systemic toxin (28 litres)
elimination techniques
II) Distribution

- Plasma Protein Binding:

 Many physiological constituent & xenobiotics bind reversibly to plasma

proteins especially albumin

D + Albumin↔ D-Albumin (Inactive) + Free D

 Only free D can pass easily through the cell membrane

 The higher the conc. of free form, the more toxic the chemicals
II) Distribution

 Plasma Protein Binding:

Class I
- Class I: dose < available albumin binding sites
(most drugs)
- Class II: dose > albumin binding sites (e.g.,
sulfonamide)
Class II
• Drugs of class II displace Class I drug molecules
from binding sites→ more toxic effect

Sulfonamides
II) Distribution

Plasma Protein Binding:

• In neonates, sulphonamides may result in an increase in the level of

free bilirubin in the blood, which will cross BBB producing brain
damage and kernicterus

• In old children & adults: This will not happen due to

conjugation of bilirubin with glucuronic acid in the
presence of glucuronyl transferase
II) Distribution
Affinity of chemicals to certain tissues
Liver and kidney
- They concentrate more amount of toxicant other than organs because they are
very important in the elimination of toxicants
Adipose tissue
- Toxicant with high lipid solubility may stored in body fat and become harmeful
when the toxicant is liberated from the adipose tissue to the circulation. E.g. DDT
thus (starvation) can rapidly increase blood conc & toxicity

Bone
- Some toxicant such as fluoride, lead & tetracycline are stored in the bone
II) Distribution

Physiological barriers
Chemicals will not uniformly distributed to the body due to specialized barriers
e .g blood brain barrier
 Endothelial cells of capillaries in tissues other than brain
have wide slit junctions allowing easy movement of
toxicant
 Brain capillaries have no slits between endothelial cells, i.e
tight junction of BBB
 Only carrier-mediated transport or highly lipophilic
toxicant enter CNS
III) Metabolism
 The process by which the administered chemical (parent compounds)
are modified by the organism by enzymatic reactions.
1ry objective: make chemical agents more water soluble and easier to
excrete
Decrease lipid solubility --> decrease amount at target
Increase ionization --> increase excretion rate --> decrease toxicity

 Bioactivation: Some chemicals are converted to compounds that

are equally active or more toxic than the parent compound
Ex: metabolites of methanol; formaldehyde & formic acid
are more toxic
REACTIONS OF METABOLISM
Phase I Phase II

Conversion of
Lipophyllic molecules
Into more polar molecules
by
oxidation, reduction and hydrolysis
reactions
Conjugation with a soluble
endogenous agent
e.g. glucuronic acid & sulphate
acetate

↑↓or unchanged
Activity Inactive compounds
III) Excretion

TOXICANT ARE EXCRETED BY:

• KIDNEY (GLOMERULAR FILTRATION & TUBULAR SECRETION): THE
MAIN EXCRETORY ORGAN
• LIVER (BILIARY EXCRETION)
• LUNG
• SWEAT
• SALIVA
• TEARS
III) Excretion

Active Secretion

Glomerular Filteration
Tubular
Reabsorption
III) Excretion
Urinary pH trapping
 The non-ionised form is easily reabsorbed particularly at DCT. So, toxicity of
certain drugs is increased by changing the pH of the urine
 Chemical adjustment of urinary pH can inhibit or enhance tubular drug reabsorption

 For example, aspirin overdose can be treated by urine alkalinization with Na

Bicarbonate (ion trapping)

 Ammonium chloride can be used as urine acidifier for basic drug (amphetamine)
overdose treatment
III) Excretion
Tubular secretion
• In the proximal renal tubule:
 Organic anionic & cationic transporters (OAT & OCT) mediate active
secretion of anionic & cationic drugs
 Penicillin is an example of actively secreted drugs
 Allopurinol competes with chlorpropamide secretion in renal tubes so
increasing its half life & its hypoglycemic effect of
III) Excretion
Biliary excretion
 Toxicant may be secreted by the hepatocytes into the bile canaliculi and then flows
into the bile duct and eventually into the small intestine & excreted in the stools e.g.
bilirubin, lead & arsenic

 If the liver is injured by disease or chemicals, the biliary excretory ability will be
reduced and accumulation of toxicant
 Another consequence of biliary excretion is that the compound comes into contact
with the gut microflora. The bacteria may metabolize the compound and convert it
into a more lipid-soluble substance which can be reabsorbed from the intestine into
the portal venous blood supply and so return to the liver. This may lead to a cycling of
the compound known as enterohepatic recirculation which may increase the toxicity
 Toxicodynamics
Target Organs: adverse effect is dependent upon the concentration of active
compound at the target site for enough time

• Not all organs are affected equally

– greater susceptibility of the target organ
– higher concentration of active compound
• Liver: high blood flow, oxidative reactions
• Kidney: high blood flow, concentrates chemicals
• Lung: high blood flow, site of exposure
• Neurons: oxygen dependent, irreversible damage
• Myocardium: oxygen dependent
• Bone marrow, intestinal mucosa: rapid divide
 Toxicodynamics
Alteration of cell
membrane
permeability
Immunotoxicity Change in enzyme
activity

Alteration of protein Modification of

synthesis carriers
Toxicodynamics

Action on nucleic
acids & their Interference with
metabolism coenzymesN

Formation of
Reactions causing reactive
depletion of GSH metabolites
 Toxicodynamics
1- Alteration of cell membrane permeability

• Toxic agent may interact with one of cell membrane component leading
to change in cell permeability such as:
• SH-containing protein: E.g. mercury & arsenic
• Lipids: causing peroxidation of fatty acid side chain. E.g. CCl 4
• Na/K ATPase pump inhibition by digoxin & lead resulting in
interference with cell membrane transport of Ca
 Toxicodynamics

2- Change in enzyme activity

 Certain toxicant may inhibit or activate specific enzymes with

consequent alterations in biochemical reactions:
 Cholinesterase inhibited reversibly by carbamate & organophosphate
 Hydrocyanic acid can bind with the Fe in the cytochrome oxidase and
arrest aerobic respiration
 Toxicodynamics

3- Modification of carriers
• Haemoglobin
• Carbon monoxide

4- Interference with coenzymes

• E.g. NADPH can be destroyed in the presence of free radicals
produced by toxicant such as CCl4
 Toxicodynamics
5- Formation of reactive metabolites
• Most xenobiotics are metabolized into inertmediate compounds.
• Sometimes, they are metabolised into reactive metabolites which react with proteins,
lipids, DNA & RNA
• EX: Paracetamol is ozidized into NAPQI and causes hepatotoxicity

6- Reactions causing depletion of GSH

• Oxidative stress is imbalance between pro-oxidants & antioxidants toward pro-
oxidants leading to accumulation of reactive metabolites.
• GSH scavenges these metabolites
• Reduction of GSH to 20-30% causes impairment of cell defense mechanisms
against toxic metabolites (Paracetamol)
 Toxicodynamics
7- Action on nucleic acids & their metabolism
• With Some toxicant produce damage of DNA or RNA and this leads to interference
with the processes of transcription and translation
• As a result the protein or enzyme structure is modified
• Damage occurring at the level of DNA results in mutation while damage at the level of
RNA causes cellular injury or death

8- Alteration of protein synthesis

• Some chemicals inhibit protein synthesis e.g. puromycin & ethionine
• Disturbance in the control or regulation of protein synthesis cause cellular injury
 Toxicodynamics

9- Immunotoxicity

• Results from repeated exposure to a particular substance

or its chemically related substances
• If this chemical is a large polypeptide, it acts as an antigen
and stimulates the body to form antibodies
• Substances other than polypeptides eg. Penicillin act as
hapten and combine with body proteins to form antigen
Thank you