Toxicity and Human Health

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Toxicity and Human Health

• Inneke Hantoro

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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
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• 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
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Potential stages in the development of toxicity
after chemical exposure
Toxicant
Delivery
Interaction with target molecule
Alteration of biological environment
Cellular dysfunction, injury
T O X I C I T Y
Dysrepair
Klassen (2001)
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Step 1Delivery

• 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.

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• Factors that can facilitate the accumulation of
  ultimate toxicants

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• 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.

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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 organelles
• reversible intracellular binding

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• 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

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• Excretion. Excretion is the removal of
  xenobiotics from the blood and their return to
  the external environment.
• Reabsorbtion.

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• 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.

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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 the
  largest organ in the body.
• Epidermis.
• Avascular, keratinized stratum corneum, 15-
• 20 cells thick, provides most toxicant
  protection.
• 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 tissue
• Respiratory system squamous epithelium, cilated
  columnar and cuboidal epithelium
• Non-keratinized, but cilated tissues and
  muscus-secreting cells provide mucociliary
  escalator

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• Nasopharyngeal.
• Nostrils, nasopharynx, oropharynx,
• laryngopharynx.
• Hairs and mucus trap gt5 µm particulates.
• Tracheobronchial.
• Trachea, bronchi, bronchioles cillial action.
• Luminal mucus aerosols and gases.
• Pulmonary
• Alveoli - high surface area gas exchange with
  
• cardiovascular system.

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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.

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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 systems
• Slow 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 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 (blood-brain,
  placental)

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Step 2Reaction 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 common binder
• Storage in bones.
• Heavy metals, like Pb
• Storage in liver.
• Blood flow, biotransformation
• Storage in the kidneys.
• Storage in fat.
• Lipophilic compounds

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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

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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 organs
• Multi-toxicant exposure may target the same organ
• The target organ may not be the site for storage

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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 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

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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 situation
• Nutritional habits
• Hereditary, previous disease therapy
• Etc.

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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.

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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 oxide
• Blockers of mitochondrial respiratory enzymes
• Cyanides, salicylic acid, gossypol

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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)
• fluoroacetates
• Emetic substances
• Apromorphine, zinc, copper sulfate
• Neurotoxicants
• Cardiotoxicants
• Selectively damage the heart
• Ex cardioglucosides, digitoxin, aconitine, etc.

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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 substances
• Damage the kidneys
• Mercury, chlorine, carbon tetrachloride, lead
• Substances that damage the bone marrow and blood
  cells
• Nirobenzene, benzene, etc.

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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

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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)
• Mutagenic
• Generation of irreversible changes in the
  hereditary materials (chromosomes, genes) of an
  organism

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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 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

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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 the cellular
  proteins.
• The cell disperses, accumulates liquid and its
  content flows out.

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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, F2 are
  very harmful to human and microorganisms.

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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).

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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 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.

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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

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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

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Neurotoxicity

• Neuroparalytic poisons
• anticholinesteratic
• Toxicants, acting with mediators or synaptic
  poisons
• Adrenaline, ephedrine, hydrazines, etc.

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