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
• bronchioles180 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 cant 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
• Shavers 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 Fl
our, 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 (1880s) "The First Operation
with Ether"
28
Chloroform (CHCl3)
Chloroform one of the earliest anesthetic
agents discontinued early 1900s 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
Exposure

• Lungs Quick to brain
• Skin Slow, irritant
• Oral e.g. alcohol

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/ind
  ex.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_at_asmalldoseof.org
Web www.asmalldoseof.org