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

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.

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

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:

  • Rigidity of luminal walls
  • 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

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

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

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.

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Jean Ford, M.D.

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