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A Small Dose of ™ Respiratory Tox An Introduction To Respiratory Toxicology Respiratory Toxicology – 06/06/05 Functional Anatomy - Upper Upper Respiratory Passages – Nose Mouth Throat Vocal cords A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Functional Anatomy - Middle Middle Respiratory Passages Trachea Bronchi Bronchioles Bronchioles narrow in Asthma Bronchitis Emphysema A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Tracheobronchial region 16 generations of conducting airways Trachea: 2.5 cm2 cross-sectional area bronchi bronchioles:180 cm2 cross-sectional area, 65,000 (216) airways Lined with ciliated epithelial cells and thin mucus layer, the ‘mucociliary escalator’ for clearance of particles Smooth muscles regulate airflow A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Gas Exchange Pulmonary region: Alveoli Alveolar ducts Respiratory bronchioles A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Asthma Bronchi A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Respiratory Function Primary • Gas exchange - oxygen, carbon dioxide, water vapor Secondary • Communication • Biotransformation of pollutants • Defense against infection and entry of airborne toxicants A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Lung Facts Major route of entry • surface area = 50-100 m2 Barrier thickness = 1 µm Affected by hazardous materials & Chemicals (solvents and particles) A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Oxygen Uptake 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 exercise, the flow rate of air is 45 L/min, and amount of oxygen taken in is 85.7 g. 24 hours – 15,000 L A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Dust Inhalation Dust particle (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] A Small Dose of Toxicology Dust mag 12,000 NASA Respiratory Toxicology – 06/06/05 Ozone Inhalation Ozone concentration is 0.1 ppm. Rate of ventilation is 10 L/min (light exercise) over 3 hrs. 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] A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Lung Volumes and Capacities Tidal Volume (VT): Volume of air inhaled/exhaled during one breath Vital Capacity (VC): Largest possible tidal volume (with maximal effort) Functional Residual Capacity (FRC): Volume of air in lungs after normal expiration Residual Volume (RV): Volume of air that can’t be expelled, even with maximal effort Total Lung Capacity (TLC): Vital Capacity + Residual Volume A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Lung Volumes and Capacities Total Lung Capacity Vital Capacity Tidal Volume Functional Residual Capacity Residual Volume Reference: Adapted from Gordon and Amdur , 1991 A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Environmental Effects 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 A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Occupational Disease Pneumoconioses - dust in the lungs, fibrosis (scarring, stiffening) generally present Coal workers (CWP) - simple or progressive Silicosis - is associated with tuberculosis, cancer Shaver’s disease - bauxite Berylliosis – beryllium; immune system Siderosis - iron; often considered benign Stannosis - tin Asbestosis - is associated with cancer A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Occupational Disease Industrial Bronchitis - chemical irritants Byssinosis - cotton processing Endotoxin in bacterial contaminant suspected Hypersensitivity pneumonitis - mold, fungi A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Occupational Disease - 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 A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Occupational Asthma One of the most common occupational respiratory diseases Caused by an agent encountered in the workplace More than 200 known etiologic agents Temporal limitation of airflow Non-specific bronchial hyperresponsiveness First described in about 460 B.C. by Hippocrates, in fishermen, farmers, woodworkers, and others A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Occupational Asthma Allergic response, may be delayed Wheeze, cough, shortness of breath Agents: animal dander, colophony, isocyanates, grain and wood dusts, anhydrides and phthalates, platinum compounds A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Occupational Asthma: Contributing Factors Host Factors Exposure Factors Job Factors Occupational Asthma Climate/ Geography Factors A Small Dose of Toxicology Adapted from Brooks, 1992 Industry Factors Respiratory Toxicology – 06/06/05 Occupational Asthma: Examples Industry/Occupation Agent(s) Milling/Baking Agriculture Health care Grain handler Laboratory worker Lumber and woodworking Paper product manufacture Airplane/sporting manufacture Painting Plastics industry Metals Industry Flour, insects, mite debris Animal antigens, dusts Latex, formaldehyde Grain, insect debris, dust Animal antigens Wood dusts (plicatic acid) Natural glues Epoxy resins Isocyanates, chromium (VI) Isocyanates, anhydrides Stainless/galvanized steel, chromium (VI) A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Bronchihal Asthma Bronchial hyperresponsiveness: exaggerated bronchoconstriction in response to various stimuli Reduced expiratory airflow Dyspnea: shortness of breath Wheezing Airway inflammation Mucus hypersecretion Various triggers: IgE mediated: dust, pollens, other allergens Non-IgE mediated: infection, exercise, air pollutants A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Respiratory Hazards- Agriculture Dusts Occupational asthma and bronchitis: grains, hay, pollen, animal dander, feces, bacterial antigens and toxins, insect and mite antigens Fibrosis: silica Chemicals Occupational asthma and bronchitis: pesticides (carbamates and organophosphates), fertilizers, antibiotics in animal feed Toxic gases Bronchitis, cough, shortness of breath, pulmonary edema: H2S, NH3, CH4 (from decomposition of urine), Asphyxiation: CO (from gasoline powered machines) A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Respiratory Hazards- Industrial Smelters Fibrosis: aluminum Squamous cell carcinoma: Nickel Foundries Occupational asthma: metals Bronchitis: Iron oxides Fibrosis: Iron oxides Welding Occupational asthma: metals (nickel),amines, chromic acid, ozone (during gas shielded arc welding) Bronchitis: Iron oxides Emphysema: cadmium oxide, ozone Fibrosis: Iron oxides A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Gas or Vapor Exposure Irritants Cause mucus membrane inflammation Examples: Ammonia, sulfur dioxide Asphyxiants Limit O2 supply to the body Examples Simple: Nitrogen, methane Chemical: carbon monoxide, hydrogen cyanide A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Historical Events - Anesthetics 1275 - Ether discovered by Spanish chemist Raymundus Lullius and called “sweet vitriol” 1500s - Paracelsus experimented (enjoyed?) with the effects of ether 1842 – First used in surgery by Crawford Williamson Long, MD, of Jefferson, Georgia, U.S. 1846 - Dr. William T.G. Morton a dentist, anaesthetized a patient for surgery at the Massachusetts General Hospital 1929 – discovery of cyclopropane 1956 – discovery of halothane in England A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 First Operation with Ether Robert Hinckley's (1880’s) "The First Operation with Ether" A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Chloroform (CHCl3) Chloroform – one of the earliest anesthetic agents – discontinued early 1900’s because of liver toxicity Cl H C Cl Cl A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Anesthetic Agents • • • • • A Small Dose of Toxicology Cyclopropane Enflurane Halothane Methoxyflurane Diethy ether Respiratory Toxicology – 06/06/05 Products – Mostly Solvents • • • • • • • • • • • A Small Dose of Toxicology Gasoline Diesel Fuel Charcoal lighter fluid Lantern fuel Grease Lubricating oils Degreasing agents Paint stripers Paint thinner Turpentine Nail polish remover Respiratory Toxicology – 06/06/05 Products – Partly Solvents • • • • • • • • • • • A Small Dose of Toxicology Glues Adhesives Oil based paints Furniture polishes Floor polishes and waxes Spot removers Metal and wood cleaners White out Computer disk cleaner Varnishes and shellacs Wood and concrete stains Respiratory Toxicology – 06/06/05 Exposure Lungs – Quick to brain Skin – Slow, irritant Oral – e.g. alcohol A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Acute Adverse Effects Obvious (high exposure) Death, loss of consciousness, paralysis, convulsion, disorientation, euphoria, giddiness, confusion. Subtle Impaired performance, depression, apathy, fatigue, A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 CNS Effects Motor – fatigue, tremor, incoordination Sensory – visual, auditory Cognitive – short and long term memory, intellectual ability Mood – depression, apathy, irritability, depression A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Chronic Adverse Effects Obvious Cancer, reproductive effects, liver and kidney damage, developmental effects, visual system damage Subtle Impaired performance, impaired memory, depression, reduced intellectual ability A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Chronic Obstructive Pulmonary Disease (C.O.P.D.) Bronchitisbronchiolitis Emphysema -inflammation -secretions -alveolar enlargement -damage to alveolar septa COP D Chronic airflow limitation resistance to expiratory flow Adapted from Robbins and Kumar, 1987 A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Regulatory Status • TLV – Threshold Limit Value • STEL – Short Term Exposure Limits (15 minute exposure) • TWA – Time Waited Average (acceptable for 8 hr day, 40 hr week) • TLV-C – Threshold Limit Value-C (ceiling not to be exceeded) A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 A Small Dose of ™ Resp Tox A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Additional Information Web Sites • American Lung Association – National http://www.lungusa.org/ • United Nations Office for Drug Control and Crime Prevention (UN ODCCP) – Access: http://www.undcp.org/odccp/index.html • U.S. Department of Labor – Occupational Safety & Health Administration (OSHA) – Access: http://www.osha.gov/SLTC/respiratoryprotection/ind ex.html - Information on respiratory protection. A Small Dose of Toxicology Respiratory Toxicology – 06/06/05 Authorship Information This presentation is supplement to “A Small Dose of Toxicology” For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: [email protected] Web: www.asmalldoseof.org A Small Dose of Toxicology Respiratory Toxicology – 06/06/05