INHALATION TOXICOLOGY Teacher: M. Abdollahi Teacher Assistant: A. Baghaei

Reference

Definitions o Respiratory Tract Toxicity Route of exposure Route of exposure o Inhalation Toxicity Target organ toxicity Target organ toxicity

Introduction o Bernardino Ramazzini Italian physician Italian physician Worked on occupational diseases Worked on occupational diseases In 1713, with regard to miners of metal he stated 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 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 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 tract

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

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

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

Gas exchange o Consists of Ventilation Ventilation Perfusion Perfusion Diffusion Diffusion

Responses of the respiratory system to toxic agents

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

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

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

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

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

Deposition Mechanisms I. Interception II. Impaction III. Sedimentation IV. Diffusion

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

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

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

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

Air Pollution

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

Types and Sources of Air Pollution o Air Pollution Chemicals added to the atmosphere by natural events or human activities in high enough concentrations to be harmful Chemicals added to the atmosphere by natural events or human activities in high enough concentrations to be harmful o Two categories Primary Air Pollutant Primary Air Pollutant Harmful substance that is emitted directly into the atmosphere Harmful substance that is emitted directly into the atmosphere Secondary Air Pollutant 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 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 o Two main sources Transportation Transportation Industry Industry o Intentional forest fires is also high

Major Classes of Air Pollutants o Particulate Material o Nitrogen Oxides o Sulfur Oxides o Carbon Oxides o Hydrocarbons o Ozone

Major Air Pollutants

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

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

Carbon Oxides and Hydrocarbons o Carbon Oxides Gases carbon monoxide (CO) and carbon dioxide (CO 2 ) Gases carbon monoxide (CO) and carbon dioxide (CO 2 ) Greenhouse gases Greenhouse gases o Hydrocarbons Diverse group of organic compounds that contain only hydrogen and carbon (ex: CH 4 - methane) Diverse group of organic compounds that contain only hydrogen and carbon (ex: CH 4 - methane) Some are related to photochemical smog and greenhouse gases Some are related to photochemical smog and greenhouse gases

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

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

Ozone Reduces Lung Function BASELINE 2HR 4HR FEV1, % CHANGE M-10

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

M-1c

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

Formation of Photochemical Smog

Sources of Smog

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

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

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

Air Quality Index DescriptorsCautionary Statement Good 0 – 50 No message Moderate 51 – 100 Unusually sensitive individuals Unhealthy for Sensitive Groups Identifiable groups at risk - different groups for different pollutants Unhealthy General public at risk; sensitive groups at greater risk Very Unhealthy General public at greater risk; sensitive groups at greatest risk

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

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

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

Acid Deposition o 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 o pH scale

How Acid Deposition Develops

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

Acid Deposition and Forest Decline

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

Indoor Air Pollution o Pollutants can be 5-100X greater than outdoors o Most common: Radon, cigarette smoke, carbon monoxide, nitrogen dioxide, formaldehyde pesticides, lead, cleaning solvents, ozone, and asbestos Radon, cigarette smoke, carbon monoxide, nitrogen dioxide, formaldehyde pesticides, lead, cleaning solvents, ozone, and asbestos