Respiratory Toxicology

Michael S. Morgan

University of Washington

Email: mmorgan@uw.edu

Respiratory System

Functional anatomyHead 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 diameterD>10 µm: deposition in head, especially with nose-

breathingD<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 bloodSO2: 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, sneezeHead and larger tracheobronchial airways; very rapid

Mucociliary systemMucus blanket propelled toward mouth by ciliated

epithelial cellsClears head and all airways in tracheobronchial regionSpeed decreases with depth in respiratory system;

slowest clearance may require 24 hours

Alveolar macrophagesSurface 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 processingEndotoxin in bacterial contaminant suspected

Hypersensitivity pneumonitis - mold, fungi

Occupational Lung Diseases

CancerBronchogenic 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