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Inhalation Toxicology

Teacher: M. Abdollahi Teacher Assistant: A. Baghaei. Inhalation Toxicology. Reference. Definitions. Respiratory Tract Toxicity Route of exposure Inhalation Toxicity Target organ toxicity. Introduction. Bernardino Ramazzini Italian physician Worked on occupational diseases

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Inhalation Toxicology

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  1. Teacher: M. Abdollahi Teacher Assistant: A. Baghaei Inhalation Toxicology

  2. Reference

  3. Definitions • Respiratory Tract Toxicity • Route of exposure • Inhalation Toxicity • Target organ toxicity

  4. Introduction • Bernardino Ramazzini • Italian physician • Worked on occupational diseases • In 1713, with regard to miners of metal he stated • the lungs and brains of that class of workers are badly affected, the lungs especially, since they take in with the air mineral spirits and are the first to be keenly aware of injury • They (workers who shovel, melt, cast and refine mined material) are liable of the same diseases, though in less acute form, because they perform their tasks in open air

  5. Overview of respiratory tract

  6. Overview of respiratory tract • Nasal Passage • Obligate nose breathers (small rodents) • Oronasal breathers (human, dogs, monkeys) • Air is warmed and humidified • As a filter for particles • P-450 isozymes have been localized in the nose of several species

  7. Overview of respiratory tract • Conducting airways • Proximal airways (Trachea and Bronchi) • ciliated cells • The nonciliated cells (mucous and serous cells) • Mucus layer is also thought to have antioxidant, acid-neutralizing, and free radical scavenging functions that protect the epithelial cells

  8. Overview of respiratory tract • Gas exchange region • Lung • In human • In rodents • Alveoli • 80–90% of the total parenchymal lung volume • adult human lungs contain an estimated 300 million alveoli

  9. Gas exchange • Consists of • Ventilation • Perfusion • Diffusion

  10. Responses of the respiratory system to toxic agents

  11. Distribution of Metabolic Competencein the Respiratory Tract • lung has substantial capabilities for both metabolic activation as well as detoxification • Total P-450 activity: 1/10 to 1/3 of liver • CYP enzymes • Phase I enzymes • Phase II enzymes

  12. GENERAL PRINCIPLES IN THE PATHOGENESIS OF LUNG DAMAGE CAUSED BY CHEMICALS Toxic Inhalants, Gases, and Dosimetry Particle Size and deposition Nanotoxicology

  13. GENERAL PRINCIPLES IN THE PATHOGENESIS OF LUNG DAMAGE CAUSED BY CHEMICALS • Toxic Inhalants, Gases, and Dosimetry • Sites of disposition of gases define the pattern of toxicity • Water solubility • SO2 • NOx and ozone

  14. GENERAL PRINCIPLES IN THE PATHOGENESIS OF LUNG DAMAGE CAUSED BY CHEMICALS • Particle size • More particles reach the deep lung, the higher is the probability of a toxic effect • Mass Median Aerodynamic Diameter (MMAD) • Larger than 5μm MMAD • 0.2–5μm MMAD

  15. GENERAL PRINCIPLES IN THE PATHOGENESIS OF LUNG DAMAGE CAUSED BY CHEMICALS • Nanotoxicology • particles with diameters of <100 nm • Ultrafine particles generally produces greater alveolar concentration

  16. Deposition Mechanisms • Interception • Impaction • Sedimentation • Diffusion

  17. Mechanisms of Respiratory Tract Injury • Oxidative Burden • Free radicals generated by Nox and SO2 • Mediators of lung toxicity • IL-1β, TGF-β, TNF-α • Airway reactivity • Bronchoconstriction caused by cigarette and air pollutants • Pulmonary edema • Acute, exudative phase of lung injury

  18. Airborne Agents That Produce Lung Injury in Humans • Asbestos • Was widely used for its highly desirable insulating and fireproofingproperties • The hazards depend on fiber length. Fibers 2μm length may produce asbestosis • Phagocytized by alveolar macrophages • Long fibers are incompletely ingested • Release of mediators by macrophages

  19. Airborne Agents That Produce Lung Injury in Humans • Silica • Inhaled particles of silicone dioxide (Silica) • Respirable silica particles (usually less than 5 μm) • dyspnea, fever, cough, and weight loss • Rapid progression of respiratory failure • Ending in deathwithin a year or two

  20. Blood-borne Agents That Cause PulmonaryToxicity in Humans • Bleomycin • Cyclophosphamide • Paraquat • 1,3 Bis (2-Chloroethyl)-1-Nitrosourea (BCNU) • Metabolism by liver • Creation of reactive metabolites • Oxidation in lung CYP system • Creation of ROS and subsequently oxidative damage • Pulmonary fibrosis

  21. Air Pollution

  22. Atmosphere as a Resource • Atmospheric Composition • Nitrogen 78.08% • Oxygen 20.95% • Argon 0.93% • Carbon dioxide 0.04% • Ecosystem services • Blocks UV radiation • Moderates the climate • Redistributes water in the hydrologic cycle

  23. Types and Sources of Air Pollution • Air Pollution • Chemicals added to the atmosphere by natural events or human activities in high enough concentrations to be harmful • Two categories • Primary Air Pollutant • Harmful substance that is emitted directly into the atmosphere • Secondary Air Pollutant • Harmful substance formed in the atmosphere when a primary air pollutant reacts with substances normally found in the atmosphere or with other air pollutants

  24. Sources of Outdoor Air Pollution • Two main sources • Transportation • Industry • Intentional forest fires is also high

  25. Major Classes of Air Pollutants • Particulate Material • Nitrogen Oxides • Sulfur Oxides • Carbon Oxides • Hydrocarbons • Ozone

  26. Major Air Pollutants

  27. Particulate Material • Thousands of different solid or liquid particles suspended in air • Includes: soil particles, lead, asbestos, sea salt, and sulfuric acid droplets • Dangerous for 2 reasons • May contain materials with toxic or carcinogenic effects • Extremely small particles can become lodged in lungs

  28. Nitrogen and Sulfur Oxides • Nitrogen Oxides • Gases produced by the chemical interactions between atmospheric nitrogen and oxygen at high temperature • Problems • Greenhouse gases • Cause difficulty breathing • Sulfur Oxides • Gases produced by the chemical interactions between sulfur and oxygen • Causes acid precipitation

  29. Carbon Oxides and Hydrocarbons • Carbon Oxides • Gases carbon monoxide (CO) and carbon dioxide (CO2) • Greenhouse gases • Hydrocarbons • Diverse group of organic compounds that contain only hydrogen and carbon (ex: CH4- methane) • Some are related to photochemical smog and greenhouse gases

  30. Ozone • Tropospheric Ozone • Man- made pollutant in the lower atmosphere • Secondary air pollutant • Component of photochemical smog • Stratospheric Ozone • Essential component that screens out UV radiation in the upper atmosphere • Man- made pollutants (ex: CFCs) can destroy it

  31. Ozone Irritates Airways • Symptoms • Cough • Sore or scratchy throat • Pain with deep breath • Fatigue • Rapid onset • Similar symptoms - people with and without asthma

  32. Ozone Reduces Lung Function 0 -20 FEV1, % CHANGE -40 -60 BASELINE 2HR 4HR M-10

  33. Ozone Causes Inflammation • Ozone reacts completely in surface layer - formsreactive oxygen molecules • Influx of white blood cells • Damages cells that line the airways • Effect is greater 24 hours after exposure • Increases airway reactivity

  34. M-1c

  35. Urban Air Pollution • Photochemical Smog • Brownish-orange haze formed by chemical reactions involving sunlight, nitrogen oxide, and hydrocarbons

  36. Formation of Photochemical Smog

  37. Sources of Smog

  38. Effects of Air Pollution • Low level exposure • Irritates eyes • Causes inflammation of respiratory tract • Can develop into chronic respiratory diseases

  39. Children and Air Pollution • Greater health threat to children than adults • Air pollution can restrict lung development • Children breath more often than adults • Children who live in high ozone areas are more likely to develop asthma

  40. Ways to Improve Air Quality • Reduce sulfur content in gasoline from its current average of 330 ppm to 30 ppm • Sulfur clogs catalytic converters • Require emission standards for all passenger vehicles • Including SUVs, trucks and minivans • Require emission testing for all vehicles • Including diesel

  41. Air Quality Index

  42. Ozone Depletion in Stratosphere • Ozone thinning/hole • First identified in 1985 over Antarctica • Caused by • human-produced bromine and chlorine containing chemicals • Ex: CFCs

  43. Effects of Ozone Depletion • Higher levels of UV-radiation hitting the earth • Eye cataracts • Skin cancer (right) • Weakened immunity • May disrupt ecosystems • May damage crops and forests

  44. Recovery of Ozone Layer • Montreal Protocol (1987) • Reduction of CFCs • Started using HFAs • Phase out of all ozone destroying chemicals is underway globally • Satellite pictures in 2000 indicated that ozone layer was recovering • Full recovery will not occur until 2050

  45. Acid Deposition • Sulfur dioxide and nitrogen dioxide emissions react with water vapor in the atmosphere and form acids that return to the surface as either dry or wet deposition • pH scale

  46. How Acid Deposition Develops

  47. Effects of Acid Deposition • Declining Aquatic Animal Populations • Thin-shelled eggs prevent bird reproduction • Because calcium is unavailable in acidic soil • Forest decline • Ex: Black forest in Germany (50% is destroyed)

  48. Acid Deposition and Forest Decline

  49. Air Pollution Around the World • Air quality is deteriorating rapidly in developing countries • Shenyang, China • Residents only see sunlight a few weeks each year • Developing countries have older cars • Still use leaded gasoline • 5 worst cities in world • Beijing, China; Mexico City, Mexico; Shanghai, China; Tehran, Iran; and Calcutta, India

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