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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
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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
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Respiratory Toxicology – 06/06/05
Gas Exchange
Pulmonary region:
 Alveoli
 Alveolar ducts
 Respiratory bronchioles
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Asthma Bronchi
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Respiratory Function
Primary
• Gas exchange - oxygen, carbon
dioxide, water vapor
Secondary
• Communication
• Biotransformation of pollutants
• Defense against infection and
entry of airborne toxicants
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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)
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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
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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]
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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]
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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
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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
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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
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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
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Respiratory Toxicology – 06/06/05
Occupational Disease
 Industrial Bronchitis - chemical irritants
 Byssinosis - cotton processing
 Endotoxin in bacterial contaminant
suspected
 Hypersensitivity pneumonitis - mold, fungi
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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
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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
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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
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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
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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)
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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
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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)
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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
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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
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Respiratory Toxicology – 06/06/05
First Operation with Ether
Robert Hinckley's (1880’s)
"The First Operation with Ether"
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Chloroform (CHCl3)
Chloroform – one of the earliest
anesthetic agents – discontinued early
1900’s because of liver toxicity
Cl
H C Cl
Cl
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Respiratory Toxicology – 06/06/05
Anesthetic Agents
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Cyclopropane
Enflurane
Halothane
Methoxyflurane
Diethy ether
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Products – Mostly Solvents
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Gasoline
Diesel Fuel
Charcoal lighter fluid
Lantern fuel
Grease
Lubricating oils
Degreasing agents
Paint stripers
Paint thinner
Turpentine
Nail polish remover
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Products – Partly Solvents
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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
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Acute Adverse Effects
Obvious (high exposure)
Death, loss of consciousness, paralysis,
convulsion, disorientation, euphoria,
giddiness, confusion.
Subtle
Impaired performance, depression,
apathy, fatigue,
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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
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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
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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