toxicity and human health 2011
TRANSCRIPT
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Toxicity
and
Human Health
Inneke Hantoro
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The induction of toxic effects largely depends
on the disposition of the substances
concerned.
Kinetic
Phase
Dynamic
Phase
Interaction of a substance with a living organism
absorption, distribution,
metabolism, andexcretion
the fate of substance in the body
interactions of the toxicant within the organism
and describes processes at organ, tissue,cellular, and molecular levels
the body has a number of defense mechanisms at
various levels of the kinetic phase, metabolism
& excretion
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Potential stages in the development of toxicity after
chemical exposure
Toxicant
Delivery
Interactionwith target
molecule
Alterationof biological
environment
Cellular
dysfunction,injury
Dysrepair
T
OX
I
C
I
T
YKlassen (2001)
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Step 1:
Delivery
Theoretically, the intensityof a toxic effect dependsprimarily on theconcentration andpersistence of the ultimate
toxicant at its site of action.
The ultimate toxicant is thechemical species thatreacts with theendogenous target
molecule(e.g., receptor,enzyme, DNA, protein,lipid) or critically alters thebiological (micro)environment, initiatingstructural and/or functionalalterations that result is
toxicity.
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Factors that can
facilitate the
accumulation of
ultimate toxicants
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AbsorptionAbsorption is the transfer of a chemical fromthe site of exposure, usually an external orinternal body surface (e.g., skin, mucosa of the
alimentary and respiratory tracts), into thesystemic circulation.
Presystemic Elimination
During transfer from the site of exposure to thesystemic circulation, toxicants may beeliminated.
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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 organellesreversible intracellular binding
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Mechanisms Opposing Distribution toa 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 adiposetissue
association with intracellular binding proteinsexport from cells
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Toxication
Biotransformation to harmful products is called
toxication or metabolic activation.
With some xenobiotics, toxication confersphysicochemical properties that adversely alter
the microenvironment of biological processes
or structures.
For example, oxalic acid formed from ethyleneglycol may cause acidosis and hypocalcaemia
as well as obstruction of renal tubules by
precipitation as calcium oxalate.
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Detoxication
Biotransformation that eliminates an
ultimate toxicant or prevents its formation is
called detoxication.
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The absorption of toxicants
Process by which the toxicants cross
the epithelial cell barriers.
Route of absorption:
Skin
Respiratory
Digestive
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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.
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Integumentary System Route
Skin, hair, nails, mammary glands. Skin is thelargest organ in the body.
Epidermis.
Avascular, keratinized stratum corneum, 15-
20 cells thick, provides most toxicantprotection.
Dermis.
Highly vascularized; nerve endings, hair
follicles, sweat and oil glands.
Hypodermis.
Connective and adipose tissue.
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Skin
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Respiratory System Route
Skin: stratified squamous epithelial tissueRespiratory system: squamous epithelium,
cilated columnar and cuboidal epithelium
Non-keratinized, but cilated tissues and
muscus-secreting cells provide mucociliaryescalator
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Nasopharyngeal.
Nostrils, nasopharynx, oropharynx,
laryngopharynx.
Hairs and mucus; trap >5 m particulates.Tracheobronchial.
Trachea, bronchi, bronchioles; cillialaction.
Luminal mucus aerosols and gases.
Pulmonary
Alveoli - high surface area gas exchangewith
cardiovascular system.
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Digestive System Route
Mouth, oral cavity, esophagus, stomach, smallintestine, 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 forabsorption.
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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).
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Distribution of toxicants in the body
Lymphatic system
Lymph capillaries, nodes, tonsils, spleen,
thymus, lymphocytes
Drain fluids from systemsSlow circulation
Cardiovascular system
Heart, arterial and venous vessels, capillaries,
blood
Fast circulation
Major distribution by blood
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In blood system, major toxicant
transport medium:
Erythrocytes (red blood cell)
Leukocytes (white blood cell)
Platelets (thrombocytes)
Plasma (non-cellular fluid)
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Factors affecting Distribution:
Physical or chemical properties oftoxicants
Concentration gradient (volume ofdistribution)
Cardiac output to the specific tissuesDetoxication reactions (protein binding)
Tissue sensitivity to the toxicant (adiposetissue, receptors)
Barriers that inhibit migration (blood-brain, placental)
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Step 2:
Reaction of
toxicants
with the
target
molecule
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Step 3: alteration of the regulatory or
maintenance function of the cell
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Storage of toxicants
Accumulation of toxicants in specific tissues.
Binding to plasma proteins.
Albumin most abundant and commonbinder
Storage in bones.
Heavy metals, like Pb
Storage in liver.
Blood flow, biotransformationStorage in the kidneys.
Storage in fat.
Lipophilic compounds
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Target Organ Toxicity
Adverse effects or disease statesmanifested in specific organs in the body
High cardiac output = higher exposure
Organs each have specialized tissues andcells
Differentiated cellular processes andreceptors
Toxicants and metabolites may havespecific reactive pathways
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Target Organ Toxicity
Toxicants do not affect all organs to the
same extent
A toxicant may have several sites of action
and target organsMulti-toxicant exposure may target the
same organ
The target organ may not be the site forstorage
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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
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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 highconcentration
The repairing system in the tissue is either
less-developed or absent to the toxicant
This tissue has receptors specific to thistoxicant receptors on the cell membrane
This tissue has an elevated physiological
sensitivity to this toxicant
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Variability of toxic response
Individual-related (subjective)
Living and working environment-
related (objective)
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Factors influencing the intensity of
toxic response
Age
Gender
Endocrine situationNutritional habits
Hereditary, previous disease &
therapyEtc.
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Types of toxic response
Local
Occurring only at the site of exposure ofthe organisms to the potentially toxicsubstance (skin, lungs, digestive tracts)
Systemic
Revealing itself after distribution of thetoxicant via the bloodstream around the
affected organism including the targetorgan or tissue, distinct from theabsorption site.
A di t th t f th i d ff t
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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 oxideBlockers of mitochondrial respiratory enzymes
Cyanides, salicylic acid, gossypol
A di t th t f th i d ff t
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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)
fluoroacetatesEmetic substances
Apromorphine, zinc, copper sulfate
Neurotoxicants
CardiotoxicantsSelectively damage the heart
Ex: cardioglucosides, digitoxin, aconitine,etc.
A di t th t f th i d ff t
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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 substancesDamage the kidneys
Mercury, chlorine, carbon tetrachloride, lead
Substances that damage the bone marrow and
blood cellsNirobenzene, benzene, etc.
A di t th t f th i d ff t
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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
B d th h t f d f ll/
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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)
MutagenicGeneration of irreversible changes in the
hereditary materials (chromosomes, genes) of
an organism
B d th h t f d f ll/
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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 ofthe 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
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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
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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 thecellular proteins.
The cell disperses, accumulates liquid
and its content flows out.
Di t i j f ll ti
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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, F2are
very harmful to human and microorganisms.
Di t i j f ll ti
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Direct injury of cell or tissue
Apoptosisthe 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).
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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
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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
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Neurotoxicity
Many toxic compounds can causeserious brain impairment. Based onthe mechanism of their effect,
toxicants that have undesirable effectto the brain can be grouped:
Neurotoxic compounds:
These compounds can disturb thefunction of nervous system
Mercury, acrylamide, hexane, CO2,methyl-n-butylketone.
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Neurotoxicity
CNS inhibitor:
Chlorinated hydrocarbons, benzene,
aceton, dietyl eter
Psychomimetics:
They can disturb psychical activities
Mescalin, phenylethylamine
derivatives, indole derivatiesCompounds that inhibiting the respiration
center
Narcotics, hydrocarbons
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Neurotoxicity
Convulsion toxicantsConvulsion in central origin
Organophosphorus pesticide
Toxicants, paralyzing transmission ofnerve impulses to the muscle
Botulinin
Toxicants, paralyzing transmission ofnerve impulses in the nerve
Tetrodotoxin
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Neurotoxicity
Neuroparalytic poisons:
anticholinesteratic
Toxicants, acting with mediators or
synaptic poisons:
Adrenaline, ephedrine, hydrazines, etc.
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Thank You