Toxicity and Human Health 2011

8/10/2019 Toxicity and Human Health 2011

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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



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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.



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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.



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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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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.

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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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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

Documents

Toxicity and Human Health 2011