An Introduction To Respiratory Toxicology

Respiratory Toxicology – 06/06/05

An Introduction To Respiratory Toxicology

A Small Dose of ™ Respiratory Tox

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

Functional Anatomy - Upper

Upper Respiratory Passages – Nose Mouth Throat Vocal cords


Functional Anatomy - Middle

Middle Respiratory Passages Trachea Bronchi Bronchioles

Bronchioles narrow in Asthma Bronchitis Emphysema


Tracheobronchial region

16 generations of conducting airways Trachea: 2.5 cm2 cross-sectional area

bronchi bronchioles:180 cm2 cross-sectional

area, 65,000 (216) airwaysLined with ciliated epithelial cells and thin

mucus layer, the ‘mucociliary escalator’ for clearance of particles

Smooth muscles regulate airflow


Gas Exchange

Pulmonary region: Alveoli Alveolar ducts Respiratory bronchioles


Asthma Bronchi


Respiratory Function

Primary • Gas exchange - oxygen, carbon

dioxide, water vapor

Secondary• Communication • Biotransformation of pollutants• Defense against infection and

entry of airborne toxicants


Lung Facts

Major route of entry• surface area = 50-100 m2

Barrier thickness = 1 µmAffected by hazardous materials &Chemicals (solvents and particles)


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


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


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]


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


Lung Volumes and Capacities

TidalVolume

FunctionalResidual Capacity

ResidualVolume

VitalCapacity

TotalLung

Capacity

Reference: Adapted from Gordon and Amdur , 1991


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


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


Occupational Disease

Industrial Bronchitis - chemical irritants Byssinosis - cotton processing Endotoxin in bacterial contaminant

suspected Hypersensitivity pneumonitis - mold, fungi


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


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


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


Occupational Asthma: Contributing Factors

OccupationalAsthma

HostFactors

ExposureFactors

Climate/Geography

Factors

IndustryFactors

JobFactors

Adapted from Brooks, 1992


Occupational Asthma: Examples

Industry/Occupation Agent(s)Milling/Baking Flour, insects, mite debrisAgriculture Animal antigens, dustsHealth care Latex, formaldehydeGrain handler Grain, insect debris, dustLaboratory worker Animal antigensLumber and woodworking Wood dusts (plicatic acid)Paper product manufacture Natural gluesAirplane/sporting manufacture Epoxy resinsPainting Isocyanates, chromium (VI)Plastics industry Isocyanates, anhydridesMetals Industry Stainless/galvanized steel,

chromium (VI)


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


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)


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


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


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


First Operation with Ether

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


Chloroform – one of the earliest anesthetic agents – discontinued early 1900’s because of liver toxicity

Chloroform (CHCl3)

CH

Cl

Cl

Cl


• Cyclopropane

• Enflurane

• Halothane

• Methoxyflurane

• Diethy ether

Anesthetic Agents


Products – Mostly Solvents

• Gasoline• Diesel Fuel• Charcoal lighter fluid• Lantern fuel• Grease• Lubricating oils• Degreasing agents• Paint stripers• Paint thinner• Turpentine• Nail polish remover


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


Exposure

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


Obvious (high exposure)Death, loss of consciousness, paralysis, convulsion, disorientation, euphoria, giddiness, confusion.

SubtleImpaired performance, depression, apathy, fatigue,

Acute Adverse Effects


Motor – fatigue, tremor, incoordination Sensory – visual, auditory Cognitive – short and long term memory,

intellectual ability Mood – depression, apathy, irritability,

depression

CNS Effects


ObviousCancer, reproductive effects, liver and kidney damage, developmental effects, visual system damage

SubtleImpaired performance, impaired memory, depression, reduced intellectual ability

Chronic Adverse Effects


Chronic Obstructive Pulmonary Disease (C.O.P.D.)

Bronchitis-bronchiolitis

CC O PO P DD

Emphysema

Adapted from Robbins and Kumar, 1987

Chronic airflow limitationresistance to expiratory flow

-inflammation-secretions

-alveolar enlargement -damage to alveolar septa


• 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


A Small Dose of ™ Resp Tox


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.


Authorship Information

For Additional Information ContactSteven G. Gilbert, PhD, DABT

E-mail: [email protected]: www.asmalldoseof.org

This presentation is supplement to “A Small Dose of Toxicology”

An Introduction To Respiratory Toxicology

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