An Introduction To Respiratory Toxicology

1. An Introduction To Respiratory Toxicology A Small Dose of ™ Respiratory Tox

2. Functional Anatomy - Upper • Upper Respiratory Passages – • Nose • Mouth • Throat • Vocal cords

3. Functional Anatomy - Middle • Middle Respiratory Passages • Trachea • Bronchi • Bronchioles • Bronchioles narrow in • Asthma • Bronchitis • Emphysema

4. 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

5. Gas Exchange • Pulmonary region: • Alveoli • Alveolar ducts • Respiratory bronchioles

6. Asthma Bronchi

7. Respiratory Function • Primary • Gas exchange - oxygen, carbon dioxide, water vapor • Secondary • Communication • Biotransformation of pollutants • Defense against infection and entry of airborne toxicants

8. Lung Facts • Major route of entry • surface area = 50-100 m2 • Barrier thickness = 1 µm • Affected by hazardous materials & • Chemicals (solvents and particles)

9. 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

10. 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] Dust mag 12,000 NASA

11. 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]

12. 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

13. Lung Volumes and Capacities Total Lung Capacity Vital Capacity Tidal Volume Functional Residual Capacity Residual Volume Reference: Adapted from Gordon and Amdur , 1991

14. 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

15. 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

16. Occupational Disease • Industrial Bronchitis - chemical irritants • Byssinosis - cotton processing • Endotoxin in bacterial contaminant suspected • Hypersensitivity pneumonitis - mold, fungi

17. 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

18. 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

19. 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

20. Occupational Asthma: Contributing Factors Host Factors Exposure Factors Job Factors Occupational Asthma Climate/ Geography Factors Industry Factors Adapted from Brooks, 1992

21. Occupational Asthma: Examples Industry/Occupation Agent(s) Milling/Baking Flour, insects, mite debris Agriculture Animal antigens, dusts Health care Latex, formaldehyde Grain handler Grain, insect debris, dust Laboratory worker Animal antigens Lumber and woodworking Wood dusts (plicatic acid) Paper product manufacture Natural glues Airplane/sporting manufacture Epoxy resins Painting Isocyanates, chromium (VI) Plastics industry Isocyanates, anhydrides Metals Industry Stainless/galvanized steel, chromium (VI)

22. 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

23. 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)

24. 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

25. 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

26. 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

27. First Operation with Ether Robert Hinckley's (1880’s) "The First Operation with Ether"

28. Chloroform (CHCl3) Cl H Cl C Cl Chloroform – one of the earliest anesthetic agents – discontinued early 1900’s because of liver toxicity

29. Anesthetic Agents • Cyclopropane • Enflurane • Halothane • Methoxyflurane • Diethy ether

30. Products – Mostly Solvents • Gasoline • Diesel Fuel • Charcoal lighter fluid • Lantern fuel • Grease • Lubricating oils • Degreasing agents • Paint stripers • Paint thinner • Turpentine • Nail polish remover

31. Products – Partly Solvents • 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

32. Lungs – Quick to brain Skin – Slow, irritant Oral – e.g. alcohol Exposure

33. Acute Adverse Effects Obvious (high exposure) Death, loss of consciousness, paralysis, convulsion, disorientation, euphoria, giddiness, confusion. Subtle Impaired performance, depression, apathy, fatigue,

34. CNS Effects • Motor – fatigue, tremor, incoordination • Sensory – visual, auditory • Cognitive – short and long term memory, intellectual ability • Mood – depression, apathy, irritability, depression

35. 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

36. Chronic Obstructive Pulmonary Disease (C.O.P.D.) Bronchitis- bronchiolitis Emphysema -alveolar enlargement -damage to alveolar septa -inflammation -secretions C O P D Chronic airflow limitation resistance to expiratory flow Adapted from Robbins and Kumar, 1987

37. 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)

38. A Small Dose of ™ Resp Tox

39. 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/index.html - Information on respiratory protection.

40. Authorship Information This presentation is supplement to “A Small Dose of Toxicology” For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: smdose@asmalldoseof.org Web: www.asmalldoseof.org