Toxicology of Respiratory system-I & II (2).pptx

Dr Heba Salem
Toxicology of
Respiratory system
PHL-537

OUTLINE
 Function of the Respiratory System
 Anatomy and Physiology of the Respiratory System
 Pulmonary Ventilation
 Effects of Toxicants on the Respiratory System
 Exposure to Respiratory Toxicants
 Immediate Responses to Respiratory Toxicants: Mechanisms
 Immediate Responses to Respiratory Toxicants: Effects on Upper and Lower
Airways
 Delayed and Cumulative Responses to Respiratory Toxicants
 Inhalation Studies

FUNCTION OF THE RESPIRATORY SYSTEM
 The primary functions of the respiratory system
are to deliver oxygen to the bloodstream, and to
remove the waste product of metabolism—
carbon dioxide.
 Other functions:
 Has a role in speech
 Has a role in the defence of the body
 Regulation of body pH
 A rapid route by which volatile xenobiotics
can reach the brain

ANATOMY AND PHYSIOLOGY OF THE RESPIRATORY
SYSTEM
 The respiratory system can be divided into two basic
parts:
 The conducting portion, is responsible for carrying
air to and from the second part
 The respiratory portion. is where the process of
gas exchange, the movement of oxygen into and
carbon dioxide out of the bloodstream, occurs.
 The lungs are highly vascularized for gases to be
exchanged between the lungs and the blood .

SYSTEM
 The conducting portion consists of:
 The nose (filter and increase the temperature of air
and add moisture to it)
 Pharynx
 Larynx (irritation causes a reflex action called cough)
 Trachea
 Bronchi and bronchioles

SYSTEM
 The respiratory portion consists of:
 The respiratory bronchioles
 The alveoli
Composed of one thin layer of epithelial tissue, with a thin
layer of elastic fibers underneath
 In the alveoli there are macrophages (digest and destroy
debris and m.o.)
The epithelial tissue contains:
Clara cells (where xenobiotic metabolism occurs)
Thin flat type I cells (the major gas exchange surface of the
alveolus)
Cuboidal type II cells
 Type II cells can divide to produce new type I cells, and can

DEFENSE MECHANISMS OF THE RESPIRATORY SYSTEM
Cilia
Mucus
Immune cells
Cytochrome P450
When type I cells are damaged, type II cells can undergo mitosis,
proliferate, and replace the damaged cells

PULMONARY VENTILATION
 Inspiration, is initiated by contraction of two muscles: the diaphragm and the
external intercostals (which extend from each rib to the rib below) size of
the thoracic cavity  thus expanding the volume of the lungs and inflating
the alveoli
 Expiration, is a passive process due to the elastic properties of the lungs.
 During expiration, the diaphragm and the external intercostal muscles relax
 the volume of the thoracic cavity, and thus the lungs
↓   the pressure
in the lungs  air is forced out of the lungs through the conducting airways

 Respiratory volumes: the amounts of air moved by the lungs and can be
measured by spirometer.
 Tidal volume (TV): the amount of air breathed in or out during normal quiet
breathing
 Inspiratory reserve volume (IRV): the additional volume of air that can be inhaled
with effort
 Expiratory reserve volume (ERV): the additional volume of air that can be exhaled
with effort
 Vital capacity = TV + IRV + ERV
 Residual volume (RV): the volume of air that always remains
in your lungs
 Total lung capacity = RV + vital capacity
Respiratory
Volumes

 The respiratory rate: the number of inspirations per minute
 The minute volume: the volume of air moved in and out per minute
= Respiratory rate X tidal volume
 Forced expiratory volume 1 (FEV1): the volume of air that can be forcibly
exhaled in a period of 1 second, following a maximum inhalation
 Many pathological conditions of the lungs affect respiratory volumes and
rates
 Restrictive conditions result from decrease in elasticity of the lungs and
cause decreases in lung volumes.
 Obstructive conditions result from blockage or narrowing of the airways
and cause decreases in airflow rates (which can be measured by an FEV1).

EFFECTS OF TOXICANTS ON THE RESPIRATORY SYSTEM
 For some toxicants, the lungs are a target only when the route of
exposure to that toxicant is inhalation.
 Other toxicants produce effects on the lungs even when exposures
occur through ingestion or absorption through the skin
 Toxicants that affect the respiratory system following inhalation can be
divided into two general categories: gases and particulates
 Exposure to these toxicants can be either acute or chronic, and effects
due to exposure may be either immediate or delayed.

EXPOSURE TO RESPIRATORY TOXICANTS
Measuring Exposure Levels
Exposures can be estimated on the basis of the concentration of the gas or the particle
in the environment and the length of exposure.
Concentrations can be expressed as:
Parts per million (ppm) (typically for gases): expresses concentration as the
volume of the gas per million volumes of air.
Weight per volume manner (for gases and suspended particles): expresses
concentration as milligrams per cubic meter of air (mg/m3
).

The American Conference of Governmental and Industrial Hygienists (ACGIH) has
developed a list of allowable exposures in the occupational setting for various
respiratory toxicants.
Threshold limit values (TLVs): specify the average maximum allowable
concentrations to which workers can be exposed without undue risk.
TLV-TWA (time-weighted average) gives the maximum allowable concentration for
exposure averaged over an 8h/day.
TLV-STEL (short-term exposure limit) gives the maximum allowable concentration
for a 15 min period
TLV-C (ceiling) gives the concentration limit that should never be exceeded

Toxicology of Respiratory system-I & II (2).pptx

Deposition of Gases
Deposition of a gas in the respiratory system depends primarily on the
water solubility of the gas.
Water-soluble gases are likely to dissolve quickly into the watery mucus
secreted by the cells lining the upper parts of the respiratory tract
Gases that are less water soluble are more likely to continue deeper into
the respiratory tract.

Deposition of particulates
 Factors affecting particle deposition in the respiratory system:
1-The size of particulates is the main factor
Very large particles (5 μm in diameter) are likely to impact on the walls
of the nasal cavity or pharynx during inspiration.
Medium-sized particles (1–5 μm in diameter) tend to settle as sediment
in the trachea, bronchi, or bronchioles as air velocity decreases in
these smaller passageways
Particles less than 1 μm in diameter typically move by diffusion into
alveoli

Deposition of particulates
2-The shape of a particle can also affect the site of deposition
3-Physiological factors influence particle deposition as well where the
narrower the airways, the more deposition will occur
4-Rapid inhalation of deep breaths (those that occur during exercise) also
increases exposure and deposition

IMMEDIATE RESPONSES TO RESPIRATORY TOXICANTS:
MECHANISMS
 There are several different mechanisms by which toxicants produce their damage
and three major mechanisms are:
1. Irritation
2. Involvement of the immune system
3. Free radical-induced damage
 The degree of reversibility of immediate responses depends directly on the degree
of damage produced in the respiratory tissue.

MECHANISMS
1.The Irritant Response
Some gases and particulates act as physical or chemical irritants that produce:
 Inflammatory response characterized by an increase in the permeability of blood
vessels and accumulation of immune system cells in the area of the damage.
 This leads to an accumulation of fluids or edema in the airways, cell death, or
necrosis
 Bronchoconstriction
 Increase in sensitivity of bronchiolar smooth muscle to other agents through
increased sensitivity of receptors to cholinergic stimulation
 Alterations in breathing patterns

MECHANISMS
2.Involvement of the Immune System
 Some toxicants may produce their effects through their interactions with the
immune system
 Proinflammatory molecules that appear to be important in the
production of immune-related damage to the lung include:
 High-mobility group protein B1 (HMGB1) which is associated with the
development of edema
 Histamine and prostaglandins that are released during an allergic
response can also produce edema, increase in the mucus secretion,
and bronchoconstriction

MECHANISMS
3.Free radical-induced damage
 Some respiratory toxicants produce damage through production of free radicals,
which can interact with membranes and other cellular constituents to produce
significant cellular damage.
 Sources of free radicals:
- High-oxygen environment such as the alveoli allow these reactions to occur
frequently, and compounds that stimulate these normal metabolic processes might
stimulate free radical production.
-Those generated through cytochrome P450 metabolism of certain xenobiotics.

MECHANISMS
Types of free radicals:
1-Reactive oxygen species (ROS) such as:
 Superoxide anion (O)2−
that is produced normally during the process of oxidative
phosphorylation and during other normal cellular processes
 Hydrogen peroxide (H2O2), is formed when the superoxide anion is further oxidized
by the enzyme superoxide dismutase
 H2O2 can also be broken down to form the hydroxyl radical (∙OH).

MECHANISMS
Types of free radicals:
2-Nitric oxide
 Play a significant role in respiratory damage and is produced in the lung by the
action of the enzyme nitric oxide synthase (NOS)
 NOS is found in a variety of lung cell types, including type II cells, macrophages,
and endothelial cells.

EFFECTS ON UPPER AND LOWER AIRWAYS
Immediate Responses: Upper Airway Effects
 Sulfur dioxide (SO2) a water-soluble irritant and a potent bronchoconstrictor that
produces swelling and edema in the upper airways, causing narrowing of the
passageways, making breathing more difficult, and increases the secretion of mucus
 Formaldehyde is another upper airway irritant. Individuals with preexisting respiratory
diseases such as asthma may be particularly susceptible to these two irritants.
 Acrolein: irritant of both upper and lower airways,
 A volatile compound that is released during heating of cooking oils, also found in
mainstream and sidestream smoke and automobile exhaust
 May also be involved in the production of chronic obstructive pulmonary
disease (COPD) and lung cancer

EFFECTS ON UPPER AND LOWER AIRWAYS
Immediate Responses: Lower Airway Effects
 Irritant gases and particles that are less water soluble, such as nitrogen dioxide
(NO2) and ozone (O3), produce accumulation of fluid in the alveoli that interferes
with gas exchange, acting as an additional barrier to diffusion of gases
 Both gases are oxidants and damage membranes through lipid peroxidation
 NO2 is slightly absorbed all along the respiratory tract, thus producing
both upper and lower airway irritation
 Paraquat
 Is quite toxic herbicide (LD50 of 30 mg/kg)
 It accumulates in and damages the lungs through all routes of absorption:
respiratory, oral, or dermal.
 It damages the cells through lipid peroxidation where it generates free radicals
and depletes NADPH

DELAYED AND CUMULATIVE RESPONSES TO
RESPIRATORY TOXICANTS
 Repeated (chronic) exposure to respiratory toxicants often leads to long-term
changes in respiratory function
 Some of which may not occur until sometime after exposure to the toxicant begins
and others that may accumulate gradually before noticeable changes occur.
 These changes may lead to obstructive or restrictive lung diseases or lung cancer
and are typically irreversible:
 Asthma & Immune related chronic conditions
 COPD
 Fibrosis and pneumoconiosis
 Lung Cancer

Asthma & Immune related chronic conditions
Asthma
 An acute effect characterized by increased sensitivity of bronchial
smooth muscle, leading to repeated episodes of bronchoconstriction
that may range from mild to severe.
 Can be induced through exposure to either allergens or irritants.
 The mechanisms may involve injury to airway epithelial cells by free
radicals. By increased production of ROS by immune system cells that
are part of the chronic inflammation response.
 A chronic predisposition to asthma may develop following exposure to
toxicants such as the chemical toluene diisocyanate (TDI)

Byssinosis (brown lung)
 Exposure to cotton dust can produce a condition called byssinosis characterized
by bronchoconstriction.
 Symptoms be most severe when a worker in a cotton mill returns to work after a
day or two off.
Hypersensitivity pneumonitis
 Symptoms are shortness of breath, fever, and chills
 Results from exposure to organic materials that trigger an immune response
localized primarily in the lower airways.
 For example: exposure to moldy hay can lead to a condition called farmer’s lung,
whereas exposure to fungus found on cheese particles may produce cheese
washer’s lung.
 Continued exposure can result in permanent lung damage in the form of fibrosis .

Chronic Obstructive Pulmonary Disease:
 Characterized by chronic cough and dyspnea
 Patients suffer from combination of chronic bronchitis and emphysema ,
airflow reduction as measured by FEV1.
 Risk for developing COPD is strongly correlated with exposure to
respiratory toxicants, with smoking as the primary risk factor
 Also, can occur due to exposure to smoke generated by cooking and
heating with open fires indoors

 Chronic bronchitis:
 Excessive secretion of mucus results from increases
in the mucus gland size and increases in numbers
of goblet cells in the respiratory tract.
 Along with this, inflammation leads to narrowing of
the airways.
 There is also a decrease in the rate of mucociliary
clearance.
 These factors result in a chronic cough and
increased susceptibility to infection.

 Emphysema
 An obstructive condition characterized by
breakdown of walls of alveoli and loss of
elasticity.
 This leads to decrease in the rate of gas exchange
(due to the decrease in alveolar surface area).
 The causes of emphysema are complex involving
proteases which are enzymes that break down
proteins.
 Smoking act through increasing protease activity

Fibrosis and Pneumoconioses:
Fibrosis
 Can occur after some years of exposure, to a number of different toxicants
that produce irritation and inflammation in the lower respiratory system
Mechanism
 Fibrosis occurs when repeated activation of macrophages leads to chronic
inflammation resulting in the recruitment of fibroblasts that produces the
rigid protein collagen.
 Accumulation of collagen interferes with ventilation (by reducing elasticity)
and with blood flow within the lung.
 Abnormal cross-linking between collagen fibers may also contribute to the
stiffness associated with fibrosis.

Pneumoconioses:
 Are diseases associated with dust exposure and characterized by fibrosis
 Silicosis:
 Is one of the most widespread and serious occupational lung diseases
caused by exposure to crystalline silicates
 Alveolar macrophages ingest the inhaled silica crystals and become
damaged resulting in the release of cytokines that attract and stimulate
fibroblasts
 Silicosis is a potential hazard for anyone whose occupations involve
mining, quarrying, blasting, grinding, or other types of stone working.

Pneumoconioses
 Asbestosis, a similar condition caused by exposure to asbestos (fibrous silicate)
 Causes damage to DNA and other cellular constituents in two ways:
 Reactive oxygen species (ROSs) are generated by direct chemical
interactions involving the surface of fibers and by immune cells as
macrophages as they phagocytize the fiber.
 ROSs then produce upregulation of cytokines such as (TNF-α) in
macrophages  induces the production of other cytokines that then
recruit fibroblasts and other cells involved in inflammation.
 Other cytokines that may also be involved in the development of
asbestosis include transforming growth factor (TGF) and interleukins 1 and
6.

Coal worker’s pneumoconiosis (CWP), black lung
 Caused by exposure to coal dust
 Characterized by the presence of black nodules in the lungs, along with
widespread fibrosis and emphysema.

Lung Cancer
 One of the leading causes of cancer deaths
 Lung cancers typically originate from airway epithelial cells either in the
center (squamous cell carcinoma) or
 periphery (adenocarcinoma) of the lung.
 Large cell carcinoma,
 Small cell carcinoma, is less common and also more rapid in growth.

Lung Cancer
 Develop in response to DNA damage by ROS and other free radicals,
radiation, or other reactive compounds.
 Chromosomal changes have been seen in a variety of lung cancers
 loss of tumor suppressor genes (such as p53 or p16)
 Activation of oncogenes (EGFR and ALK)

Lung Cancer
 The greatest risk factor for lung cancer is exposure to tobacco smoke (10–20 times
the non-smokers)
 Smoking interacts in an additive or, in some cases, synergistic manner with other
risk factors for lung cancer (such as asbestos).
 Children and nonsmoking spouses of smokers are more likely to suffer from
respiratory problems and lung cancer than children and spouses of nonsmokers.
 There are approximately 69 known carcinogens in tobacco which include:
polycyclic aromatic hydrocarbons such as benzo(a)pyrene, nitrosamines,
heterocyclic amines, formaldehyde, and benzene; pesticides such as DDT and vinyl
chloride; and metals such as nickel, chromium, cadmium, and lead.

INHALATION STUDIES
 Inhalation chambers are used to study effects of airborne toxicants.
 An inhalation chamber consists of one or more areas in which animals
are held for exposure, along with some apparatus for delivery of the
toxicant to be tested.
 Static test systems, the toxicant is simply introduced and mixed into
the atmosphere in a closed chamber.
 This method is relatively simple
 But disadvantages:
 The tendency for oxygen to be depleted and carbon dioxide to
accumulate in the chamber


INHALATION STUDIES
Dynamic test system
 Air is constantly circulated through the exposure chamber, with the
toxicant being introduced into the entering airstream.
 Gases may be directly mixed in with incoming air; particles may be
introduced either as a dry dust or suspended in droplets of water.
 Concentration of gases and concentration and size of particles can be
monitored by sampling within the chamber
 The level of exposure can be adjusted by altering either flow rate
through the chamber or rate of addition of the toxicant to the airstream

INHALATION STUDIES
 In the chamber: the whole body of the animal may be exposed to the
toxicant or just the head or neck.
 Toxicants may also be injected directly into the trachea
 Parameters tested to assess respiratory function in test animals:
 Respiratory rates and volumes (vital capacity, minute volume, FEV1,
etc.),
 Oxygen and carbon dioxide levels and blood pH can also be used
 Washing of the lungs with physiological saline (a technique called
bronchoalveolar lavage) can supply cells for in vitro analysis of cellular
function.

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