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Respiratory Toxicology

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

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Respiratory Toxicology

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  1. Respiratory Toxicology Michael S. Morgan University of Washington Email: mmorgan@uw.edu

  2. 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.

  3. 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

  4. 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

  5. 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)

  6. 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.

  7. 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]

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. Respiratory Disease Identification • Relationship to environmental and occupational causes • Influence of tobacco smoke • Spirometry is principal surveillance tool • Exposure and occupational histories are critical

  13. 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

  14. 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

  15. 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

  16. 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

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