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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
Teacher: M. Abdollahi

Teacher Assistant: A. Baghaei

Inhalation Toxicology
definitions
Definitions
  • Respiratory Tract Toxicity
    • Route of exposure
  • Inhalation Toxicity
    • Target organ toxicity
introduction
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
overview of respiratory tract1
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
overview of respiratory tract2
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
overview of respiratory tract3
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
gas exchange
Gas exchange
  • Consists of
    • Ventilation
    • Perfusion
    • Diffusion
distribution of metabolic competence in the respiratory tract
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
general principles in the pathogenesis of lung damage caused by chemicals
GENERAL PRINCIPLES IN THE PATHOGENESIS OF LUNG DAMAGE CAUSED BY CHEMICALS

Toxic Inhalants, Gases, and Dosimetry

Particle Size and deposition

Nanotoxicology

general principles in the pathogenesis of lung damage caused by chemicals1
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
general principles in the pathogenesis of lung damage caused by chemicals2
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
general principles in the pathogenesis of lung damage caused by chemicals3
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
deposition mechanisms
Deposition Mechanisms
  • Interception
  • Impaction
  • Sedimentation
  • Diffusion
mechanisms of respiratory tract injury
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
airborne agents that produce lung injury in humans
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
airborne agents that produce lung injury in humans1
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
blood borne agents that cause pulmonary toxicity in humans
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
atmosphere as a resource
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
types and sources of air pollution
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
sources of outdoor air pollution
Sources of Outdoor Air Pollution
  • Two main sources
    • Transportation
    • Industry
  • Intentional forest fires is also high
major classes of air pollutants
Major Classes of Air Pollutants
  • Particulate Material
  • Nitrogen Oxides
  • Sulfur Oxides
  • Carbon Oxides
  • Hydrocarbons
  • Ozone
particulate material
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
nitrogen and sulfur oxides
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
carbon oxides and hydrocarbons
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
ozone
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
ozone irritates airways
Ozone Irritates Airways
  • Symptoms
    • Cough
    • Sore or scratchy throat
    • Pain with deep breath
    • Fatigue
  • Rapid onset
  • Similar symptoms - people with and without asthma
ozone reduces lung function
Ozone Reduces Lung Function

0

-20

FEV1, % CHANGE

-40

-60

BASELINE

2HR

4HR

M-10

ozone causes inflammation
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
urban air pollution
Urban Air Pollution
  • Photochemical Smog
    • Brownish-orange haze formed by chemical reactions involving sunlight, nitrogen oxide, and hydrocarbons
effects of air pollution
Effects of Air Pollution
  • Low level exposure
    • Irritates eyes
    • Causes inflammation of respiratory tract
  • Can develop into chronic respiratory diseases
children and air pollution
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
ways to improve air quality
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
ozone depletion in stratosphere
Ozone Depletion in Stratosphere
  • Ozone thinning/hole
    • First identified in 1985 over Antarctica
  • Caused by
    • human-produced bromine and chlorine containing chemicals
    • Ex: CFCs
effects of ozone depletion
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
recovery of ozone layer
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
acid deposition
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
effects of acid deposition
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)
air pollution around the world
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
indoor air pollution
Indoor Air Pollution
  • Pollutants can be 5-100X greater than outdoors
  • Most common:
    • Radon, cigarettesmoke, carbon monoxide, nitrogen dioxide, formaldehydepesticides, lead, cleaning solvents, ozone, and asbestos