Respiratory Toxicology
Michael S. Morgan
University of Washington
Email: mmorgan@uw.edu
Respiratory System
Functional anatomy
Head airways (upper respiratory passages): nose,
mouth, throat, bounded by vocal cords
Tracheobronchial tree: trachea, bronchi, bronchioles;
site of narrowing in asthma, bronchitis, emphysema
Gas Exchange (pulmonary) region: alveoli, alveolar
ducts, respiratory bronchioles; the acinus consists
of one respiratory bronchiole plus all alveoli distal to
it; primary site of gas exchange; site of damage in
fibrosis, pneumonia, edema.
Respiratory function
Primary:
Gas exchange - oxygen, carbon dioxide, water
vapor
Secondary:
Communication
Biotransformation of some hormones, drugs, and
pollutants
Defense against infection and entry of airborne
toxicants
Cardiovascular system
A key partner in accomplishing gas exchange:
Primary distribution system for metabolic gases,
nutrients, absorbed agents
Heart, blood vessels, blood (role of hemoglobin)
Evaluation: heart rate, blood pressure,
electrocardiogram, exercise stress test,
angiography, chemical markers of muscle
damage
Respiratory system factors
Major route of entry - surface area = 50-100 m2
Barrier thickness = 1 µm on average
Affected by many hazardous materials
Under neurologic and chemical (O2, CO2, pH) control
Hypoventilation - underbreathing, relative to metabolic
need
Hypoxia - too little oxygen in air
Evaluation: pulmonary function tests, eg spirometry; chest
X-ray and CT imaging, allergen challenge,
bronchoalveolar lavage (evaluation of harvested cells),
NO production (marker of inflammation)
Quantitative Aspects
Ventilation and oxygen uptake:
For a 70 kg person at rest, the flow rate of air in and out
is 7.5 L/min, or 450 L/hour; the flow rate of oxygen
into the blood is 21.5 g/hour
During 30 minutes of aerobic exercise by the same person,
the flow rate of air is 45 L/min, and amount of oxygen
taken in is 85.7 g.
In a 24 hour day, for the same person, the volume of air
inhaled and exhaled is, on average, 15,000 L.
Accomplishing this requires lungs that are flexible, with a
thin membrane between air and blood, and airways that
are have minimal obstruction.
Inhalation Dosimetry
Using the flow rates given:
If the average PM10 concentration is 100 µg/m3, then the
mass inhaled is 1.5 mg dust/day/70 kg body weight
[100 µg/m3 x 15 m3 /day = 1.5 mg dust]
If the ozone concentration is 0.1 ppm for three hours
during the AM, and the rate of ventilation during this
period is 10 L/min (light exercise) then the mass inhaled
and deposited on the respiratory surfaces is 0.36
mg/day. (0.1 ppm ozone = 0.2 mg/m3)
[0.2 mg/ m3 x 180 min x .010 m3/min = 0.36 mg]
Deposition of Inhaled Agents
Particle aerodynamic diameter
D>10 µm: deposition in head, especially with nose-breathing
D<10 µm: increasing penetration to tracheobronchial and gas
exchange regions; minimum in deposition for D ≈ 0.5 µm
Gas or vapor solubility in mucus and blood
SO2: head deposition
O3: distal airway and alveolar deposition
Breathing pattern and pathway (nose v mouth)
Increasing flow rate enhances deposition via impaction in
head and larger tracheobronchial airways; decreasing flow
rate enhances deposition by diffusion and settling in
alveolar spaces.
Clearance of Deposited Agents
Cough, sneeze
Head and larger tracheobronchial airways; very rapid
Mucociliary system
Mucus blanket propelled toward mouth by ciliated epithelial
cells
Clears head and all airways in tracheobronchial region
Speed decreases with depth in respiratory system; slowest
clearance may require 24 hours
Alveolar macrophages
Surface resident cells in alveoli; ingest deposited particles,
carry them to mucociliary blanket; >24 hours.
May result in gastrointestinal absorption
Respiratory Responses to
Exposure
Altered secretions - reduction in airway diameter, slowed
clearance: chemical irritants
Airway constriction - reduction in airway diameter,
coughing; chemical irritants, allergens
Slowed clearance - reduced ciliary action, impaired
macrophage activity: irritants, cytotoxic agents
Cell damage - increased membrane permeability to fluids,
loss of surface area, decreased lung expansion;
corrosive agents
Neoplasia - uncontrolled cell growth, invasion of
neighboring tissue, airway narrowing, decreased lung
expansion: carcinogens
Classification of Respiratory
Disease
1. Obstructive: narrowing of airways at one or more
locations causes reduced air flow or increased work of
breathing. Chronic bronchitis, emphysema, asthma,
reactive airway disease
2. Restrictive: stiffening of the flexible tissue of the
lungs causes reduced lung volume, reduced air flow or
increased work of breathing, thickened membranes.
Fibrosis, cancer, pneumonia, tuberculosis
3. Vascular: changes in mechanical properties of blood
vessels causes increased blood pressure, fluid leakage.
Pulmonary edema, heart failure
4. Regulatory: failure of control system, hypoventilation.
Respiratory Disease
Identification
Relationship to environmental and occupational
causes
Influence of tobacco smoke
Spirometry is principal surveillance tool
Exposure and occupational histories are critical
Effects of Environmental
Agents
Asthma - pollen, irritant chemicals
Chronic Bronchitis - cigarette smoke
Retarded Growth of the Respiratory System in Children ozone, oxides of nitrogen
Elevated Frequency of Respiratory Infections - ozone,
particulate matter
Aggravation of Existing Respiratory or Cardiovascular
Disease - carbon monoxide, fine/ultrafine particles,
sulfate
Cancer - cigarette smoke
Asphyxiation - gases that displace oxygen: CO2
Occupational Lung Diseases
Pneumoconioses - dust in the lungs, fibrosis
(scarring, stiffening) generally present
Coal workers (CWP) - simple or progressive
Silicosis - may be associated with tuberculosis, cancer
Shaver’s disease - bauxite
Berylliosis - immune system is involved
Siderosis - iron; often considered benign
Stannosis - tin
Asbestosis - may be associated with cancer
Occupational Lung Diseases
Industrial Bronchitis - chemical irritants
Occupational Asthma Allergic response, may be delayed (ca. 12 hours)
Wheeze, cough, shortness of breath
Agents: animal dander, colophony, isocyanates, grain
and wood dusts, anhydrides and phthalates, platinum
compounds
Byssinosis - cotton processing
Endotoxin in bacterial contaminant suspected
Hypersensitivity pneumonitis - mold, fungi
Occupational Lung Diseases
Cancer
Bronchogenic cancer: initial site in airway; asbestos,
ionizing radiation, coke oven emissions, nickel carbonyl;
strong synergism between asbestos and tobacco smoke
Mesothelioma: initial site is in visceral pleura (outer lining of
lungs); few causes other than asbestos
Asphyxiation - interference with oxygen uptake, delivery
or utilization
Simple - displacement of oxygen by inert gas, eg methane,
nitrogen, acetylene
Chemical - carbon monoxide, cyanides: interfere with
oxygen transport or cellular respiration