Chapter 3

Routes of Exposure

Introduction

• Exposure alone does not determine whether the substance will

have toxic effects. In general, for any substance to have its

effects in an organism it must first be observed.

• Absorption occurs when a substance passes into a cell or into the

circulatory system regardless of the route of exposure. It is

entry into the cell or circulatory system that initiates those

processes associated with distribution, metabolism, and

elimination of the substance and the development of any toxic

effects.

A Generalized Illustration of the Cell

Basic Cell Structure and Function (1)

• The cell structures are important in absorption,

metabolism, and elimination of toxic substances.

• Exposure to toxic substances occurs daily,

however, absorption of the toxic substance must

occur in order for toxic effects to be observed.

Basic Cell Structure and Function (2)

• Plasma cell membrane

– The membrane is composed

primarily of phospholipid

molecules (75%), protein

(20%), and carbohydrates

(5%).

– The proteins appear to “float”

within the double layer of

phospholipid molecules,

wither singly or in pairs.

– These proteins can act as cell

receptors, or as carrier

molecules that attract and

transport substances across

the cell membrane.

– Water-soluble molecules and

electrically charge ions may

pass.

Basic Cell Structure and Function (3)

– The cell membrane is selectively permeable. Selective permeability is

a property of the cell membrane that allows some substances to cross

the cell membrane and prevents the crossing of others.

– Four major factors affecting the ease with which a substance move

across the cell membrane.

• Size of the molecule

• Solubility of molecule in lipids

• Electrical charge of ions and molecules

• Carrier molecules

– This occurs regardless of size, lipid solubility, or electrical charge.

Basic Cell Structure and Function (4)

• Endoplasmic reticulum (ER)

– It is associated with the intracellular (within the cell) transport, storage, and

secretion of molecules.

– Many chemical reactions occur on the surface of these membranes.

– In most cells the ER is associated with other cellular structures called the

ribosomes which are the site of protein synthesis.

– Enzymes and other proteins synthesized by the ribosomes may play an

important role in the active and passive transport processes associated with the

cell membrane as well as in the biotransformation of toxic substances.

Basic Cell Structure and Function (5)

• Mitochondria

– The mitochondrion is variable in shape. There are spherical

and rod-shaped mitochondria.

– The mitochondrion is double-membrane structure; its inner

membrane is the site of many important chemical reactions,

the most important of which are those associated with the

production of energy in the form of molecules called

Adenosine Triphosphate (ATP).

Basic Cell Structure and Function (6)

• Passive mechanisms

– The actual movement of the substances across the cell membrane will be

the result of either passive transport or active transport mechanisms.

– Passive transport

• It does not require the expenditure of energy by the cell to move a substance

across the cell membrane.

• Concentration gradients result in passive movement of substances across the

cell membrane.

• Diffusion, osmosis, and facilitated diffusion are all examples of passive

transport.

• http://www.northland.cc.mn.us/biology/Biology1111/animations/transport1.ht

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– Diffusion is the net movement of molecules from an area of higher

concentration to an area of lower concentration.

– Osmosis is the net movement of water (a solvent) molecules from a region

of higher water concentration to a region of lower water concentration.

– Facilitated diffusion is the net movement of a substance, using a carrier

molecule, across a cell membrane.

Basic Cell Structure and Function (7)

• Active transport mechanisms

– Active transport mechanisms expend energy and move substances against a

concentration gradient.

– This mechanism is thought to be important in the absorption of metals in

the digestive tract.

– Phagocytosis is another process where a particle, located outside the cell,

can be transported into the cell. This process requires the expenditure of

energy. The particle is surrounded by extensions of the cell called

pseudopodia.

• It is an important mechanism used by white blood cells to remove or destroy

harmful substances such as asbestos or silica which may enter the respiratory

system.

– Pinocytosis is similar to phagocytosis in that the cell membrane is involved

in moving substances from the outside to the inside of the cell, also with an

expenditure of energy.

• The cell membrane simply folds inward in response to contact with liquid, forming a vesicle

that subsequently releases the liquid into the cell.

Pathways of Exposure (1)

--- Dermal Absorption

• Exposure to toxic substances usually occurs by one of three

major pathways: dermal absorption, inhalation, and

ingestion.

• Dermal absorption

– The most common path of exposure to toxic substances is by contact

with the skin.

– The skin is composed of three main parts:

• Epidermis

– The outer layer composed of several cell layers, called the epidermis.

• Dermis

– An inner and thicker layer, the dermis, which contains a number of structures

including blood vessels, hair follicles, sweat, and sebaceous (oil) glands

• Subcutaneous layer

Pathways of Exposure (2)

--- Dermal Absorption

• The outermost layer of the epidermis is called stratum

corneum (cornified layer).

– The cells of the epidermis do not contain any blood vessels: they must

therefore obtain their oxygen and nutrients from the blood vessels located in

the underlying dermis. The lack of a direct blood supply is a contributing

factor to the death of the cells.

– As the cells die, a specialized protein called keratin forms from protein

interacting with enzymes located in the cells. Keratin gives the epidermis its

rough, impermeable characteristic.

– The ability of a toxic substance to penetrate the stratum corneum

determines the rate at which the substance will be absorbed by the skin.

Pathways of Exposure (3)

--- Dermal Absorption

• Dermis

– The second layer of the skin is the dermis, sometimes referred to

as the true skin. The dermis is composed primarily of connective

tissue. This tissue binds the skin to the bone and muscle.

– Blood vessels are distributed throughout the dermis and are

responsible for supplying nutrients to the cells of the dermis and

the epidermis.

– The dermis is the source of oxygen and of nutrients for the

epidermis.

– Also found in the dermis are other structures such as the hair

follicles, sweat glands, and sebaceous glands.

– The contraction of the smooth muscles associated with the hair

follicles results in “goose bumps.”

Pathways of Exposure (4)

--- Dermal Absorption

• Subcutaneous fatty tissue

– This layer provides a cushion for the underlying structures and

allows the skin to move to some extent.

– The subcutaneous fatty tissue contributes to the connection of the

dermis to the underlying tissue such as the muscle.

Pathways of Exposure (5)

--- Dermal Absorption

• Factors affecting absorption – The ability of the skin to absorb a toxic substance is

dependent upon two major factors:

• The condition of the skin, and

• The chemical nature of the toxic substance.

– The outer portion of the epidermis is composed of several layers of thin flat cells.

• The outermost cells are dead and are continuously replaced from below, approximately every two weeks.

• The outer layer serves as an effective barrier.

• Because of its relative impermeability it retards the diffusion of gases, water, and chemicals, preventing many types of toxic substances from entering the body.

Pathways of Exposure (6)

--- Dermal Absorption

• Factors affecting absorption (continued)

– Physical damage to the protective barrier, such as a cut or

an abrasion, allows toxic substances to easily penetrate the

epidermis and enter the dermis.

– Acids, such as sulfuric and nitric acid, as well as strong

bases, such as sodium hydroxide, are examples of toxic

substances that are capable of breaking down the outer

layers of the epidermis.

– Repetitive exposure to soaps, detergents, and organic

solvents may result in water loss and dryness of the skin;

this can enhance absorption of toxic substances.

Pathways of Exposure (7)

--- Dermal Absorption

• Inorganic chemicals, e.g., Cd, Pb, and Cr, are a class of toxic

substances that is not readily absorbed through intact, healthy

skin. However, metallic mercury is absorbed across the skin

and into the bloodstream, where it can produce systemic

effects.

• Organic chemicals dissolved in water do not easily penetrate

the skin because the skin is impermeable to water.

• Organic solvents, such as paint thinner or gasoline, are easily

absorbed through the epidermis because they are lipid-soluble

and therefore penetrate the cell membrane readily.

Pathways of Exposure (8)

--- Inhalation

• Perhaps the easiest, most rapid, and most direct route of

exposure is by inhalation.

• The lining of the respiratory tract is not effective in preventing

absorption of toxic substances into the body.

• The respiratory tract is composed of the nasal cavity, pharynx,

larynx, trachea, primary bronchi, bronchioles, and alveoli or

air sacs.

Pathways of Exposure (9)

--- Inhalation

• Mucous cells and cilia are the primary protective barriers to

particulates in the respiratory system.

• Alveoli are the primary site of exchange of toxic substances in

the respiratory tract.

• Factors affecting absorption

– Both the entry of airborne toxicants into the circulatory system and

the distribution to the body tissues depend upon several factors:

• concentration of the toxicant in the air;

• solubility of the toxicant in the blood and tissue;

• the toxicant’s molecular or particular size;

• respiration rate;

• duration of exposure; and

• functional integrity of the respiratory tract.

Pathways of Exposure (10)

--- Inhalation

• Many organic solvent vapors such as benzene and chloroform

are very soluble in the bloodstream and rapidly diffuse from

the longs into the blood.

• Many types of particulates such as silica, fiberglass, or

asbestos, are either almost or completely insoluble.

• The particles are phagocytized or engulfed by white blood

cells found in the respiratory tract. After engulfing the particle,

these cells may pass through the cell membrane.

Pathways of Exposure (11)

--- Inhalation

• An individual’s respiratory rate can affect the amount of toxic substance absorbed, especially when the substance is readily soluble in the blood.

• Increasing the respiratory rate will increase the amount of chloroform absorbed, while it would have little effect on absorption of ethylene because of its low solubility.

Pathways of Exposure (12)

--- Ingestion

• Ingestion of toxic substances other than those contained in

food is uncommon; when it does occur it is usually done

accidently or unknowingly.

• Ingestion also takes place indirectly as a result of swallowing

materials removed from the respiratory tract by ciliary activity.

Pathways of Exposure (13)

--- Ingestion

• Digestive tract

– It is composed of five major areas:

• mouth and pharynx

• esophagus

• stomach

• small intestine

• large intestine

– Absorption of toxic substances in the digestive tract

occurs primarily in the small intestine.

– The small intestine is divided into three segments: the

duodenum, the jejunum, and the ileum.

– The duodenum is the first portion of the small intestine

and is approximately 10 to 12 in long.

Pathways of Exposure (14)

--- Ingestion

• The plicae circulares, villi, and microvilli increase the surface area

(200 m2) in the small intestine, which facilitates the absorption of

substances into the bloodstream.

• Very little absorption of toxic substances occurs in the large intestine.

• The amount of toxic substance absorbed as a result of ingestion varies.

For example, 10 percent of the lead ingested is absorbed. Ingestion of

cadmium or chromium results in 1.5 percent and 1.0 percent being

absorbed, respectively.

Pathways of Exposure (15)

--- Ingestion

• Factors affecting absorption – The epithelial lining of the small intestine is only one cell thick. This enhances the

absorption rate of toxicants in the small intestine.

– Lipid solubility and molecular size are also important in determining how

efficiently toxic substances are transported across the digestive tract epithelium and

into the bloodstream.

– Competition may occur between the essential nutrients and various types of

toxicants for the carrier molecule used during active transport and facilitated

diffusion.

– Another important factor affecting absorption is the length of time food containing

the toxicant remains in the small intestine.

Eye (1)

• The eye is composed primarily of three layers of tissue.

– The outer layer consists of dense connective tissue that gives shape

to the eye. This tissue is referred to as the sclera and – in the front

of the eyeball – forma into the transparent cornea.

• It is the cornea that the first comes into contact with toxic substances and is

damaged.

– The middle layer is called the choroid; in the front of the eye it

forms the ciliary bodies as well as the pigmented iris, which gives

color to the eyes.

– The innermost layer, the retina, is composed of the sensory tissue

of the eye that are involved in producing images we see.

Eye (2)

– Two compartments that contain an aqueous fluid-like substance

called the aqueous humor and a transparent jelly-like substance

called the vitreous humors, and forming part of the barrier

between these two substances, is a transparent oval structure called

the lens.

• The aqueous humour is a thick watery substance filling the space between

the lens and the cornea.

• The hyaloid artery is a branch of the ophthalmic artery, which is itself a

branch of the internal carotid artery. It is contained within the optic stalk of

the eye and extends from the optic disc through the vitreous humor to the

lens. Usually fully regressed before birth, its purpose is to supply nutrient

to the developing lens in the growing fetus.

– The cornea, the humors, and the lens are all transparent and allow

light from the exterior to be focused on the retina to form images.

Eye (3)

• Depending on the amount of damage done, the cornea may be able to

repair itself. This process is slow because the cornea does not have a

direct blood supply. All nutrients and oxygen must diffuse through the

aqueous humor in the anterior chamber to the corneal epithelium in

order for the damaged tissue to be repaired.

Other Pathways of Exposure

• Intravenously (into a vein, iv)

• Intramuscularly (into the muscle, im)

• Intraperitoneally (into the peritoneal cavity, ip)

• Intradermally (into the skin, id)

• Subcutaneously (under the skin, )

Diffusion

Osmosis (1)

Osmosis (2)

Phagocytosis

• Phagocytosis in three steps:

1. Unbound phagocyte surface

receptors do not trigger

phagocytosis.

2. Binding of receptors causes them

to cluster.

3. Phagocytosis is triggered and the

particle is taken up by the

phagocyte.

Pinocytosis

Anatomy of Skin

Respiratory System

Gastrointestinal

Tract

Cross Section of the Small Intestine

Anatomy of Eye