RESPIRATORY TOXICOLOGY - Angelfire
RESPIRATORY TOXICOLOGY
JEAN G. FORD, M.D
CLASS HANDOUT
2-9-2000
INTRODUCTION
1. Primary function of the lung is to provide a means for the exchange of oxygen and carbon dioxide
2. Toxicants can enter respiratory system as gases solids or liquid aerosols
3. Lung receives all of the cardiac output, speeding distribution to other organs
4. Direct actions of the toxicants can be acutely and chronically important to health
ENVIRONMENTAL EXPOSURE ROUTES
Dermal
Oral
Inhalation
THE LUNG IN SYSTEMIC TOXICOLOGY
Inhalation toxicology-
Lung as route of systemic absorption
Pulmonary toxicology
Lung as a primary target organ
AIR COMPOSITION
Nitrogen 78.09%
Oxygen 20.94%
Argon 0.93%
Carbon dioxide 0.03%
STRUCTURE OF THE RESPIRATORY SYSTEM
3 Major divisions
▪ Nasopharyngeal
▪ Tracheobroncial
▪ Pulmonary
[pic]
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CONDUCTING AIRWAYS STRUCTURE
At least 8 different types of epithelial cells coated by thin layer of mucus (form secretory cells along airways) Beating of cilia moves blanket upward, mucociliary escalator removes particles.
[pic]
The Acinus is the basic functional unit of the human lung
• Basic functional unit of mammalian lungs
• Area of gas exchange takes place
• Consists of respiratory bronchioles, alveolar ducts and alveolar sacs
• Hundreds of alveoli with associated capillaries, lymphatic and supportive tissue
• Human adult lung has 200,000 acini
• Total surface area in adult lung 140-150 m2 or 70X that of skin or size of a tennis court
[pic]
The Alveolar Sac
• Surfactant lining fluid
• Alveolar epithelium and its basement membrane
• Vascular endothelium and its basement membrane
• Total thickness 0.4-2.5 microns
Lung Cell Types
40 different types
Conducting Airways
1. Ciliated epithelial cells
2. Mucus secreting cells
Mucus Blanket
1. Goblet cells
2. Serous epithelial cells
3. Gland cells-both mucus and serous
4. Nonciliated bronchiolar cells (Clara cells)
Respiratory Cell
(+) ( -)
O2 Virus
Ca++Na+K+ Bacterial Infection
Digital glycosides Alcohol
Aminophylline Cigarette smoke
Sympathomimetic Dehydration
Amines Atropine
Cholinergics
Exercise CO2, carbon monoxide, SO2, O3,
Airway Smooth muscle
Mostly in conducting airways beneath epithelial cells
Also walls of respiratory bronchioles and at alveolar duct openings
Function:
o Rigidity of luminal walls
o Regulation of airflow and ventilation
The relaxation and contraction of airway smooth muscle is controlled by neurogenic stimuli
e.g. sympathetic vagal and by locally released cellular mediators
Examples of cellular mediators are:
1. Eicosanoids regulate SM tone both in homeostasis and during inflammation
2. Histamine, tachykinnins, PAF only during inflammation
Alveolar surface
Luminal Side
Type I epithelial cells
Type II epithelial cells
Type I epithelial cells
• Few organelles
• Very thin (.1-.3μm)
• Covers 93% of alveolar surface area
Type II epithelial cells
• More numerous than type I
• Have ER, Golgi apparatus and numerous multivesicular bodies, and many large osmophilic multilamellated inclusions or cytosomes
• Synthesize and release surfactant regulate surface tension
• Progenitor for type I cell
Alveolar Macrophages
• Phagocytic cells; free in alveoli
• Ingest inhaled particulate material
• Main clearance mechanism for pulmonary region
• Infectious particles usually killed
• Role in tissue repair
• Mediators release following oxidant injury promote type II cells and collagen deposition
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Electron micrograph of lung. The alveolus is separated by blood capillary (C) by a thin margin of the type I epithelial cell (I). Note the closeness of approach of these two compartments at M. A type II cell (2) can be seen containing lamelli bodies (L) presumed to be storage site for lung surfactant.
BAL Cell Types
Figure showing typical lung volumes and flows. There is considerable variation around these values
[pic]
PHYSICAL CLASSIFICATION OF INHALED TOXIC MATERIALS- I
GAS=in gaseous state at RT and pressure
VAPOR= gaseous phase of material that is originally a solid or liquid at RT and P
AEROSOL= relatively stable suspension of solid particles or liquid droplets in air
DUSTS=solid particles formed by grinding, milling or blasting
PHYSICAL CLASSIFICATION OF INHALED TOXIC MATERIALS –II
FUMES= formed by combustion, sublimation, or condensation of vaporized material
SMOKE=produced by combustion of organic materials
MISTS AND FOGS= aerosols of liquid droplets formed by condensation of liquid on particulate nuclei in the air or by uptake of liquid by hygroscopic particles
Complex mixtures is the rule
ABSORPTION AND DISTRIBUTION OF GASES
FACTORS:
1. Concentration in inhaled air
2. Duration of exposure
3. Solubility
4. Level of activity
CLASSIFICATION OF GASES AND VAPORS
1. Irritants
2. Asphyxiants
Irritants- Health Effects
Produce inflammation in the mucus membranes
Primary Irritants- little systemic effect; respiratory action is far in excess of any systemic toxic action
Secondary Irritants- produce irritant effect on respiratory mucous membranes, but local irritant effect is overshadowed by systemic effects resulting from absorption
Asphyxiants-Health Effects
-Materials that deprives the body of oxygen
Simple asphyxiants-physiologically inert gases, which in sufficient quantity exclude adequate oxygen, supply
Chemical asphyxiants- render body incapable of utilizing an adequate supply of oxygen. Toxic at concentration far below level needed for damage from simple asphyxiants. e.g. Carbon monoxide and cyanide.
Aerosol behavior
Predominant factor affecting deposition is particle size
Motion of particles is related to their size, density and shape
Aerosols
Mechanism of deposition
1. Sedimentation: under the influence of gravity. Speed of fall proportional to particle density and square diameter
2. Diffusion: random movement induced by surrounding gas molecule. Inversely proportional to particle diameter, but independent of density
3. Inertia. Depends on particle density and diameter squared
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Parameters influencing particle deposition. (From Carett L.J.): The vital sacs: Alveloar clearance mechanisms in inhalation toxicology. In Blood, FR. [ed]: Essays in Toxicology Vol 3. Academic Press Inc., New York 1972.
This handout is also available at website
For additional questions and Comments Please email
Jean Ford, M.D.
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Nasopharynx: Begins at anterior nares and extends to the level of larynx.
Lined by vascular ciliated columnar epithelium and mucus glans. Larger inhaled particles handled by impaction and filtration by nasal hairs; conditions incoming air by warming and humidification; absorbs water-soluble gases.
The tracheobronchial tree--includes trachea, bronchi and bronchioles. Serves as conducting airways to the alveoli where gas exchange takes place.
The conducting airways are lined by ciliated columnar epithelium and coated with thin layer of mucus secreted by Goblet cells and mucus secreting cells. The mucus covering terminates at the level of alveoli.
The surface of airway serves as a mucociliary escalator, moving particles deep from the lung to the oral cavities where they can be swallowed and excreted.
The branching pattern as shown is critical in determining the deposition of particles and absorption of gases by respiratory tract.
The airways are unique: diameter decreases as airways divide, though the surface area increases.
Cell
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