Toxicity

and
Human Health
Inneke Hantoro

Toxicity
Toxicity is the potential of a chemical to induce
an adverse effect in a living organism e.g.,
man.
How a toxicant enters
an organism

Toxicity

How it interacts with

target molecule

How organism deals

with the insult

The induction of toxic effects largely depends

on the disposition of the substances
concerned.
Interaction of a substance with a living organism

Kinetic
Phase

absorption, distribution,
metabolism, and excretion
the fate of substance in the body
the body has a number of defense mechanisms at
various levels of the kinetic phase, metabolism
& excretion

Dynamic
Phase

interactions of the toxicant within the organism

and describes processes at organ, tissue,
cellular, and molecular levels

Potential stages in the development of toxicity after

chemical exposure
Toxicant

Delivery

Interaction
with target
molecule

Alteration
of biological
environment

Cellular
dysfunction,
injury

Dysrepair
Klassen (2001)

T
O
X
I
C
I
T
Y

Step 1:
Delivery
Theoretically, the intensity
of a toxic effect depends
primarily on the
concentration and
persistence of the ultimate
toxicant at its site of action.
The ultimate toxicant is the
chemical species that
reacts with the
endogenous target
molecule (e.g., receptor,
enzyme, DNA, protein,
lipid) or critically alters the
biological (micro)
environment, initiating
structural and/or functional
alterations that result is
toxicity.

Factors that can

facilitate the
accumulation of
ultimate toxicants

Absorption
Absorption is the transfer of a chemical from
the site of exposure, usually an external or
internal body surface (e.g., skin, mucosa of the
alimentary and respiratory tracts), into the
systemic circulation.

Presystemic Elimination
During transfer from the site of exposure to the
systemic circulation, toxicants may be
eliminated.

Distribution to and away from the

target
Mechanisms facilitating distribution to a
target:
the porosity of the capillary endothelium
specialized membrane transport
accumulation in cell organelles
reversible intracellular binding

Mechanisms Opposing Distribution to

a Target
Distribution of toxicants to specific sites
may be hindered by several processes,
including:
binding to plasma proteins
specialized barriers
distribution to storage sites such as adipose
tissue
association with intracellular binding proteins
export from cells

Excretion. Excretion is the removal of

xenobiotics from the blood and their
return to the external environment.
Reabsorbtion.

Toxication
Biotransformation to harmful products is called
toxication or metabolic activation.
With some xenobiotics, toxication confers
physicochemical properties that adversely alter
the microenvironment of biological processes
or structures.
For example, oxalic acid formed from ethylene
glycol may cause acidosis and hypocalcaemia
as well as obstruction of renal tubules by
precipitation as calcium oxalate.

Detoxication
Biotransformation that eliminates an
ultimate toxicant or prevents its formation is
called detoxication.

The absorption of toxicants

Process by which the toxicants cross
the epithelial cell barriers.
Route of absorption:
Skin
Respiratory
Digestive

The absorption of toxicants

Absorption through skin, lung or intestinal
tissue is followed by passage into the
interstitial fluid.
Interstitial fluid (15%), intracellular fluid
(40%), blood plasma (8%)
Toxicants is absorbed & enters the lymph
or blood supply and is mobilized to other
parts of the body.
Toxicant can enter local tissue cells.

Integumentary System Route

Skin, hair, nails, mammary glands. Skin is the
largest organ in the body.
Epidermis.
Avascular, keratinized stratum corneum, 1520 cells thick, provides most toxicant
protection.
Dermis.
Highly vascularized; nerve endings, hair
follicles, sweat and oil glands.
Hypodermis.
Connective and adipose tissue.

Skin

Respiratory System Route

Skin: stratified squamous epithelial tissue
Respiratory system: squamous epithelium,
cilated columnar and cuboidal epithelium
Non-keratinized, but cilated tissues and
muscus-secreting cells provide mucociliary
escalator

Nasopharyngeal.
Nostrils, nasopharynx, oropharynx,
laryngopharynx.
Hairs and mucus; trap >5 m particulates.
Tracheobronchial.
Trachea, bronchi, bronchioles; cillial
action.
Luminal mucus aerosols and gases.
Pulmonary
Alveoli - high surface area gas exchange
with
cardiovascular system.

Digestive System Route

Mouth, oral cavity, esophagus, stomach, small
intestine, rectum, anus.
Residence time can determine site of toxicant
entry/injury.
Mouth (short); small intestine (long).
Absorption of toxicants can take place
anywhere, but much of the tissue structure in
the digestion system is specially designed for
absorption.

Digestive System Route

Tissue differentiation.
Mucosa
Avascular, s. squamus or columnar
epithelium.
In some regions villi and microvilli
structure aids in absorption
(high surface area).
Submucosa
Blood, lymph system interface.
Muscularis (movement).
Serosa (casing).

Distribution of toxicants in the body

Lymphatic system
Lymph capillaries, nodes, tonsils, spleen,
thymus, lymphocytes
Drain fluids from systems
Slow circulation

Cardiovascular system
Heart, arterial and venous vessels, capillaries,
blood
Fast circulation

Major distribution by blood

In blood system, major toxicant

transport medium:

Erythrocytes (red blood cell)

Leukocytes (white blood cell)
Platelets (thrombocytes)
Plasma (non-cellular fluid)

Factors affecting Distribution:

Physical or chemical properties of
toxicants
Concentration gradient (volume of
distribution)
Cardiac output to the specific tissues
Detoxication reactions (protein binding)
Tissue sensitivity to the toxicant (adipose
tissue, receptors)
Barriers that inhibit migration (bloodbrain, placental)

Step 2:
Reaction of
toxicants
with the
target
molecule

Step 3: alteration of the regulatory or

maintenance function of the cell

Storage of toxicants
Accumulation of toxicants in specific tissues.
Binding to plasma proteins.
Albumin most abundant and common
binder
Storage in bones.
Heavy metals, like Pb
Storage in liver.
Blood flow, biotransformation
Storage in the kidneys.
Storage in fat.
Lipophilic compounds

Target Organ Toxicity

Adverse effects or disease states
manifested in specific organs in the body
High cardiac output = higher exposure
Organs each have specialized tissues and
cells
Differentiated cellular processes and
receptors
Toxicants and metabolites may have
specific reactive pathways

Target Organ Toxicity

Toxicants do not affect all organs to the
same extent
A toxicant may have several sites of action
and target organs
Multi-toxicant exposure may target the
same organ
The target organ may not be the site for
storage

The main target organs for the

systemic toxicity of xenobiotics are:
Skin, mucous membrane
Lungs
Liver, kidney
Bone marrow
Immune system
Nervous system (central & peripheral)
Cardiovascular system
Reproductive system
Muscle and bones

Why an organ or tissue is sensitive to a

particular toxicants?
The toxicants accumulates preferably in this
organ/tissue
Inactive pro-toxicants is activated in this
organ/ tissue by phase I enzymes in high
concentration
The repairing system in the tissue is either
less-developed or absent to the toxicant
This tissue has receptors specific to this
toxicant receptors on the cell membrane
This tissue has an elevated physiological
sensitivity to this toxicant

Variability of toxic response

Individual-related (subjective)
Living and working environmentrelated (objective)

Factors influencing the intensity of

toxic response
Age
Gender
Endocrine situation
Nutritional habits
Hereditary, previous disease &
therapy
Etc.

Types of toxic response

Local
Occurring only at the site of exposure of
the organisms to the potentially toxic
substance (skin, lungs, digestive tracts)
Systemic
Revealing itself after distribution of the
toxicant via the bloodstream around the
affected organism including the target
organ or tissue, distinct from the
absorption site.

According to the nature of their adverse effect

on the target organs, the toxicants can be
divided as:
(1)
Irritants
Cause damage to the eyes & mucous
membranes, ex: bromine, chlorine, ammonia,
etc.
Corrosive substances
Corrode the skin & mucous membranes
Substances that cause toxic pulmonary edema
Chlorine, ammonia, nitrogen oxide
Blockers of mitochondrial respiratory enzymes
Cyanides, salicylic acid, gossypol

According to the nature of their adverse effect

on the target organs, the toxicants can be
divided as:
(2)
Inhibitors of thiol enzymes
Heavy metals
Blockers of Krebs cycle (citrate cycle)
fluoroacetates
Emetic substances
Apromorphine, zinc, copper sulfate
Neurotoxicants
Cardiotoxicants
Selectively damage the heart
Ex: cardioglucosides, digitoxin, aconitine,
etc.

According to the nature of their adverse effect

on the target organs, the toxicants can be
divided as:
(3)
Hepatotoxic substances
Damage the liver
Carbon tetrachloride, chloroform,etc.
Nefrotoxic substances
Damage the kidneys
Mercury, chlorine, carbon tetrachloride, lead
Substances that damage the bone marrow and
blood cells
Nirobenzene, benzene, etc.

According to the nature of their adverse effect

on the target organs, the toxicants can be
divided as:
(4)
Asphyxiants
Substances that cause a reduction of bloods
ability to bind and transport oxygen
Anticoagulants
Substances that disturb blood coagulation
Dicumarine, heparin, etc.
Hemolytic substances
Mushroom toxicants, phenyl-hydrazine,
saponins, etc.
Histamine and antihistaminic compounds

Based on the character of damage of a cell/

an organism, the toxic effects can be grouped
as (1):
Generally toxic
Damage of the organism as a whole
Dystrophic
Causing the aging cells or tissues
Genotoxic
Alteration of the genetic material (DNA, RNA)
Mutagenic
Generation of irreversible changes in the
hereditary materials (chromosomes, genes) of
an organism

Based on the character of damage of a cell/

an organism, the toxic effects can be grouped
as (2):
Carcinogenic
Genaration of malignant tumors
Gonadotropic
Harming and inhibiting the development of
the germ cells
Teratogenic
Evoking disorders in the embryonal
development of an organism
Sensibilizating
Making an organism ultrasensitive to this
compound, resulting in allergic reactions and
diseases

According to the final result, toxic

responses can be grouped as:
Direct injury of cell or tissue
Biochemical damage
Neurotoxicity
Immunotoxicity
Teratogenicity
Genetic toxicity
Carcinogenicity
Endocrine disruption

Direct injury of cell or tissue

Decomposition of cells (necrosis)
An irreversible process consisting of
degeneration of the cell, fragmentation
of the nucleus, and denaturation of the
cellular proteins.
The cell disperses, accumulates liquid
and its content flows out.

Direct injury of cell or tissue

Mechanism:
The formation of an intermediate that
reacts with definite cell components like
structural proteins.
Examples:
CN- ion or Pb can interact with the
respiratory system of a cell --- leads to the
death of a cell
Strong alkalis or acids
Strong oxidizers: ozone (O3), Cl2, Br2, F2 are
very harmful to human and microorganisms.

Direct injury of cell or tissue

Apoptosis the programmed cell
death
Normal process for tissue renewal but it
can be evoked by certain substances
Example: trans-resveratrol (in grape
wines) and its relatives (glucosides, etc).

Biochemical damage
Biochemical injury cause:
Degeneration of a single cell
Influencing vital function of metabolism
such as respiration
The death of organism:
Disruption of cell metabolism
Deficiency of several organs

Neurotoxicity
Compounds that have a toxic effect
on the nervous system:
Toxicants of the central nervous system
(CNS)
Toxicants of the peripheral nervous
system (PNS)
Toxicants of a combined effect

Neurotoxicity
Many toxic compounds can cause
serious brain impairment. Based on
the mechanism of their effect,
toxicants that have undesirable effect
to the brain can be grouped:
Neurotoxic compounds:
These compounds can disturb the
function of nervous system
Mercury, acrylamide, hexane, CO2,
methyl-n-butylketone.

Neurotoxicity
CNS inhibitor:
Chlorinated hydrocarbons, benzene,
aceton, dietyl eter
Psychomimetics:
They can disturb psychical activities
Mescalin, phenylethylamine
derivatives, indole derivaties
Compounds that inhibiting the respiration
center
Narcotics, hydrocarbons

Neurotoxicity
Convulsion toxicants
Convulsion in central origin
Organophosphorus pesticide

Toxicants, paralyzing transmission of

nerve impulses to the muscle
Botulinin

Toxicants, paralyzing transmission of

nerve impulses in the nerve
Tetrodotoxin

Neurotoxicity
Neuroparalytic poisons:
anticholinesteratic

Toxicants, acting with mediators or

synaptic poisons:
Adrenaline, ephedrine, hydrazines, etc.

Thank You