There are three principal routes of entry for toxins into the human body: percutaneous (through the skin), respiratory (through the lungs), and oral (through the mouth). Toxins penetrate the initial barrier (skin, lungs, or gastrointestinal tract) and enter the bloodstream which distributes them throughout the body. The rate and extent of absorption depends on factors like the substance's solubility, the duration of exposure, and whether it is taken up in food. Once inside the body, toxins can cause harm by damaging tissues directly or through systemic toxicity after entering circulation.

1. Mode of Entry of Toxins
• From the environmental point of view, the three principal
routes of entry of xenobiotics into the human body are
– percutaneous,
– respiratory, and
– oral.
• In multicellular animals, the extracellular space is filled with
interstitial fluid.
• Thus, it enters interstitial fluid after penetrating the initial
cellular barrier (such as skin, intestinal mucosa, or the lining
of the respiratory tract).
• From the interstitial fluid, the compound penetrates the
capillaries and enters the bloodstream, which distributes it
throughout the body.

2. Percutaneous Route
• The skin forms a protective barrier
that separates the rest of the body
from the environment.
• penetration of the skin by most
substances is slow,
• The skin consists of three layers:
– the outermost protective layer, the
epidermis;
– the middle layer, consisting of a
highly vascularized connective tissue
called the dermis; and
– the innermost layer, consisting of a
mixture of adipose and connective
tissue, called the hypodermis.
• In addition, the skin contains
epidermal appendages (hair follicles,
sebaceous glands, and sweat glands
and ducts) that penetrate into the
dermal layer.

3. • Three possible routes of percutaneous absorption
are
– diffusion through the epidermis into the dermis,
– entry through sweat ducts, and
– entry along the hair-follicle orifices.
• because of large surface area, absorption through
the epidermal cells is the major route of entry of
toxins.
• The main obstacle to percutaneous penetration of
water and xenobiotics is stratum corneum.
• This membrane is made up of several layers of
dried, flattened keratinocytes.
• All entry of substances through the stratum
corneum occurs by passive diffusion across several
cell layers.

4. • Polar substances are believed to penetrate cell
membranes through the protein;
• nonpolar ones enter through the lipid matrix
• Hydration of the stratum corneum increases its
permeability for polar substances.
• Electrolytes enter mainly in a nonionized form,
• Many lipophilic substances, such as carbon tetrachloride
and organophosphate insecticides, readily penetrate the
stratum corneum.
• In general, gases penetrate skin more readily than
liquids and solutes.
• Solids do not penetrate as such.
• Percutaneous absorption is a time-dependent process
so, duration of exposure to a xenobiotic is critical.

5. Respiratory Route
• The respiratory system consists of three
regions:
– nasopharyngeal,
– tracheobronchial,
– and pulmonary.
• The nasopharyngeal canal is lined by ciliated
epithelium through which mucous glands are
scattered.
• The role of this region is to remove large
inhaled particles and to increase the humidity
and temperature of inhaled air.
• The tracheobronchial region consists of the
trachea, bronchi, and bronchioles.
• They are lined with two types of cells: ciliated
epithelium and mucus-secreting goblet cells.
• The function of these cells is to propel foreign
particles from the deep parts of the lungs to
the oral cavity, where they can be either
expelled with the sputum or swallowed;

6. • The pulmonary region consists of respiratory bronchioles
, alveolar ducts and clusters of alveoli
• Alveoli can be described as little bubbles about 150–350
mm in diameter in which the exchange of gases between
the environment and the blood takes
• Three types of cells present in the alveolar region are
important:
– squamous alveolar lining cells (called Type I pneumocytes),
– surfactant-producing cells (called Type II pneumocytes), and
– freely floating phagocytic macrophages.
• Type II pneumocytes, in addition to producing
surfactants are involved in the repair of injuries.
• Blood capillaries are in intimate contact with the alveolar
lining cells, so that gases as well as solutes can easily
diffuse between them.

7. • Inhaled xenobiotics can exert their harmful action either
by damaging respiratory tissue or by entering the
circulation and causing systemic toxicity.
• water-soluble gases are removed, to a certain extent, in
the nasopharyngeal and tracheobronchial region.
• this removal protects the lower respiratory system, it
does not prevent the entry of these gases into the blood.
• Poorly water-soluble gases, reach the alveoli.
• The amount of a toxin delivered to the lungs (in gaseous
form, as liquid aerosols, or as particles) depends on the
concentration of the toxin in the air and on the minute
volume of respiration.
• The minute volume is a product of tidal volume (i.e.,
normal respiratory volume, about 500 mL) and the
number of breaths per minute (about 15).
• Another important factor affecting diffusion rate is the
solubility of the gas in blood.

8. • Toxins can also reach alveoli as liquid aerosols.
• If they are lipid-soluble, they readily cross alveolar membranes by passive
diffusion.
• The toxicity of particulate matter depends on the size of the particles.
• Particles larger than 5 mm are deposited in the nasopharyngeal region and
are either expelled by sneezing or propelled into the oral cavity, where they
are swallowed or expelled in the sputum.
• Particles 2–5 mm in size are deposited in the tracheobronchial region. They
are cleared by the mucociliary escalator and eventually end up being
expelled in the sputum or swallowed.
• Particles 1 mm or smaller are deposited in alveoli.
• Then the free or phagocytized particles may be carried to the
tracheobronchial region, where they are removed from the respiratory
system by the mucociliary escalator.
• Alternately, both free and phagocytized particles may pass through small
• (0.8–1.0 nm) intercellular spaces between alveolar lining cells and enter
• the lymphatic system.
• Particles resulting from combustion frequently carry adsorbed polycyclic
aromatic hydrocarbons (PAHs), some of which are carcinogens.
• These adsorbed hydrocarbons may dissolve in alveolar fluid and enter the
circulation as solutes.

9. Oral Route
• The absorption of compounds taken orally begins in the
mouth and esophagus.
• However, in most cases the retention time in this area is so
short that no significant absorption takes place.
• In the stomach, compounds are mixed with food, acid,
gastric enzymes, and bacteria.
• All of these can alter the toxicity of the chemical, either by
influencing absorption or by modifying the compound.
• It has been demonstrated that there are quantitative
differences in toxicity, depending upon whether compounds
are administered with food or directly into the empty
stomach
• Most food absorption takes place in the small intestine.

10. • The gastrointestinal tract possesses specialized carrier
systems for certain nutrients such as carbohydrates, amino
acids, calcium, and sodium.
• Some xenobiotics use these routes of passage through the
cells; others enter through passive diffusion.
• Lipid-soluble organic acids and bases are absorbed by
passive diffusion only in nonionized form.
• Particles several nanometers in diameter can be absorbed
from the gastrointestinal tract by pinocytosis and enter the
circulation via the lymphatic system.
• A percentage of xenobiotics absorbed in the gastrointestinal
cells may be biotransformed before entering the circulatory
system;
• The absorbed compounds may enter the circulation either
via the lymphatic system, which eventually drains into the
bloodstream,
• or via the portal circulation, which carries them to the liver.