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.

Toxicity

How a toxicant enters an organism

How it interacts with target molecule

How organism dealswith the insult

The induction of toxic effects largely depends on the disposition of the substances concerned.

KineticPhase

DynamicPhase

Interaction of a substance with a living organism

absorption, distribution, metabolism, and excretion

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 atvarious levels of the kinetic phase, metabolism

& excretion

Potential stages in the development of toxicity after chemical exposure

Toxicant

Delivery

Interactionwith targetmolecule

Alteration of biologicalenvironment

Cellulardysfunction,

injury

Dysrepair

TOXICITYKlassen (2001)

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 proteinsspecialized barriersdistribution 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.

ToxicationBiotransformation 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, 15-

20 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 RouteSkin: 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 μm particulates.Tracheobronchial.– Trachea, bronchi, bronchioles; cillial action.– Luminal mucus aerosols and gases.Pulmonary– Alveoli - high surface area gas exchange with

cardiovascular system.

Digestive System RouteMouth, 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 systemLymph capillaries, nodes, tonsils, spleen, thymus, lymphocytes

Drain fluids from systems

Slow circulation

Cardiovascular systemHeart, 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 toxicantsConcentration gradient (volume of distribution)Cardiac output to the specific tissuesDetoxication reactions (protein binding)Tissue sensitivity to the toxicant (adipose tissue, receptors)Barriers that inhibit migration (blood-brain, 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 binderStorage in bones.

Heavy metals, like PbStorage in liver.

Blood flow, biotransformationStorage in the kidneys.Storage in fat.

Lipophilic compounds

Target Organ Toxicity

Adverse effects or disease states manifested in specific organs in the bodyHigh cardiac output = higher exposureOrgans each have specialized tissues and cellsDifferentiated cellular processes and receptorsToxicants 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 environment-related (objective)

Factors influencing the intensity of toxic response

Age

Gender

Endocrine situation

Nutritional habits

Hereditary, previous disease & therapy

Etc.

Types of toxic response

LocalOccurring 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 enzymesHeavy metals

Blockers of Krebs cycle (citrate cycle)fluoroacetates

Emetic substancesApromorphine, zinc, copper sulfate

NeurotoxicantsCardiotoxicants

Selectively damage the heartEx: 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 blood’s 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 toxicantsConvulsion in central originOrganophosphorus 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…