1. Respiratory Toxicology – 06/06/05 An Introduction To Respiratory Toxicology A Small Dose of ™ Respiratory Tox

2. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Functional Anatomy - Upper Upper Respiratory Passages – Nose Mouth Throat Vocal cords

3. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Functional Anatomy - Middle Middle Respiratory Passages Trachea Bronchi Bronchioles Bronchioles narrow in  Asthma  Bronchitis  Emphysema

4. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Gas Exchange Pulmonary region: Alveoli Alveolar ducts Respiratory bronchioles

6. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Asthma Bronchi

7. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Respiratory Function Primary Gas exchange - oxygen, carbon dioxide, water vapor Secondary Communication Biotransformation of pollutants Defense against infection and entry of airborne toxicants

8. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Lung Facts Major route of entry surface area = 50-100 m 2 Barrier thickness = 1 µm Affected by hazardous materials & Chemicals (solvents and particles)

9. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Dust Inhalation Dust particle (PM10) concentration is 100 µg/m 3, then the mass inhaled is 1.5 mg dust/day/70 kg body weight. [100 µg/m 3 x 15 m 3 /day = 1.5 mg dust] Dust mag 12,000 NASA

11. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology  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 Lung Volumes and Capacities

13. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Lung Volumes and Capacities Tidal Volume Functional Residual Capacity Residual Volume Vital Capacity Total Lung Capacity Reference: Adapted from Gordon and Amdur, 1991

14. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Occupational Disease  Industrial Bronchitis - chemical irritants  Byssinosis - cotton processing  Endotoxin in bacterial contaminant suspected  Hypersensitivity pneumonitis - mold, fungi

17. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Occupational Asthma: Contributing Factors Occupational Asthma Host Factors Exposure Factors Climate/ Geography Factors Industry Factors Job Factors Adapted from Brooks, 1992

21. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Occupational Asthma: Examples Industry/OccupationAgent(s) Milling/BakingFlour, insects, mite debris AgricultureAnimal antigens, dusts Health careLatex, formaldehyde Grain handlerGrain, insect debris, dust Laboratory workerAnimal antigens Lumber and woodworkingWood dusts (plicatic acid) Paper product manufactureNatural glues Airplane/sporting manufactureEpoxy resins PaintingIsocyanates, chromium (VI) Plastics industryIsocyanates, anhydrides Metals IndustryStainless/galvanized steel, chromium (VI)

22. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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 Toxicology – 06/06/05 A Small Dose of Toxicology 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 Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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 Historical Events - Anesthetics

27. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology First Operation with Ether Robert Hinckley's (1880’s) "The First Operation with Ether"

28. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Chloroform – one of the earliest anesthetic agents – discontinued early 1900’s because of liver toxicity Chloroform (CHCl 3 ) C H Cl

29. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Cyclopropane Enflurane Halothane Methoxyflurane Diethy ether Anesthetic Agents

30. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Exposure  Lungs – Quick to brain  Skin – Slow, irritant  Oral – e.g. alcohol

33. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Obvious (high exposure) Death, loss of consciousness, paralysis, convulsion, disorientation, euphoria, giddiness, confusion. Subtle Impaired performance, depression, apathy, fatigue, Acute Adverse Effects

34. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology  Motor – fatigue, tremor, incoordination  Sensory – visual, auditory  Cognitive – short and long term memory, intellectual ability  Mood – depression, apathy, irritability, depression CNS Effects

35. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Obvious Cancer, reproductive effects, liver and kidney damage, developmental effects, visual system damage Subtle Impaired performance, impaired memory, depression, reduced intellectual ability Chronic Adverse Effects

36. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Chronic Obstructive Pulmonary Disease (C.O.P.D.) Bronchitis- bronchiolitis C O P O PD Emphysema Adapted from Robbins and Kumar, 1987 Chronic airflow limitation resistance to expiratory flow -inflammation -secretions -alveolar enlargement -damage to alveolar septa

37. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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) Regulatory Status

38. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology A Small Dose of ™ Resp Tox

39. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology 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.

40. Respiratory Toxicology – 06/06/05 A Small Dose of Toxicology Authorship Information For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: smdose@asmalldoseof.org Web: www.asmalldoseof.org This presentation is supplement to “A Small Dose of Toxicology”