EFFECTS ON THE RESPIRATORY TRACT

1
EFFECTS ON THE RESPIRATORY TRACT
Yves Alarie, Ph.D Professor Emeritus
University of Pittsburgh,USA
2
A. BRIEF LOOK AT ANATOMY AND PHYSIOLOGY
3
B. ACUTE EFFECTS A convenient and practical way
to classify airborne chemicals is by taking the
first level of the respiratory tract (from nose
to alveoli) at which they act as the exposure
concentration increases from zero.(1)
a) Sensory Irritants i) Definition Chemical which
when inhaled via the nose will stimulate
trigeminal nerve endings, evoke a burning
sensation of the nasal passage and inhibit
respiration. Also will induce coughing from
laryngeal stimulation and lachrymation from
corneal stimulation.
4
ii) Other Characteristics At high
concentration, particularly on moist facial skin,
they will induce a burning sensation. Some have
odor and taste (SO2). Many will induce airways
constriction, usually at higher
concentration. iii) Other Terms Used to Describe
Their Action Upper respiratory tract irritant,
nasal or corneal stimulant, common chemical sense
stimulant, chemogenic pain stimulant, suffocant,
lachrymator, tear gas, sternutator, "eye, nose
and throat" irritant.
5

iv) Typical Examples Chloracetophenone,
o-chlorobenzylidene malononitride,
ß-nitrostyrene, diphenylaminoarsine, sulfur
dioxide, ammonia, acrolein, formaldehyde.
v) Mechanisms All reactive (i.e.,
toward nucleophilic groups such as SH or cleaving
S-S bonds in proteins) chemicals will be potent
sensory irritants except oxidants such as ozone,
nitrogen dioxide. Also phosgene and sulfur
mustard are not sensory irritants. These are all
pulmonary irritants, see below. Chemicals of low
reactivity (solvents) are in general weak sensory
irritants. Several mechanisms have been proposed
by which both reactive and nonreactive chemicals
stimulate the sensory irritant receptor.36
6

• vi) Potency
• Their potency can be obtained by measuring the
  concentration needed to decrease the respiratory
  rate by 50 (RD50) in exposed male Swiss Webster
  mice using a body plethysmograph technique.37
  This bioassay became a standard method in 1984.38

7

• vii) Extrapolation to Humans
• The RD50 values obtained for 41 industrial
  chemicals are very well correlated with Threshold
  Limit Values (TLVs) established for the
  protection of industrial workers. The RD50 value
  multiplied by 0.03 will yield a value close to
  the TLV.39 Therefore 0.03 RD50 yields the
  likely highest level to be permitted in industry
  to prevent sensory irritation, and by extension
  to prevent any other toxic effect to occur. This
  has been recently confirmed for 89 industrial
  chemicals.40

8

• viii) Estimation of Potency
• The RD50 can be estimated for nonreactive
  chemicals (solvents) from their physical
  properties, particularly vapor pressure, their
  gas/hexadecane partition coefficient or gas/olive
  oil partition coefficient but not gas/water
  partition coefficient41,42. Furthermore, the
  potency of their mixtures can be estimated
  easily43.
• ix) Typical Results and Extrapolation to Humans
• The following pages present different aspects
  of this approach and extrapolation of the results
  to humans.

9

• b) Bronchoconstrictors
• (Airways Constrictors).
• i) Definition
• They act primarily on the conducting airways
  and should probably be called "airways
  constrictors". They may act on the larger or
  smaller airways causing their constriction and as
  a result will increase resistance to airflow in
  and out of the lung (increase in airway
  resistance). If acting on the smaller airways
  some regions of the lungs may be closed to
  ventilation resulting in air trapping in the
  lungs, and a decrease in dynamic lung compliance
  will result.

10

• ii) Mechanisms
• Their action may be via a direct effect on
  airways smooth muscles, by axonal reflex,
  vago-vagal reflexes following stimulation of
  vagal nerve endings, by liberation of histamine
  or other mediators.
• iii) Other Effects
• Increase mucus secretions, induce inflammatory
  reaction.
• iv) Typical Examples
• Histamine and cholinergic agonists, sulfur
  dioxide, following sensitization by allergens
  such as foreign proteins or chemicals acting as
  haptens (toluene diisocyanates, trimellitic
  anhydride, etc., see below).

11

• v) Potency
• Their potency can be evaluated by measuring
  airway resistance and lung compliance or by
  measuring specific airway conductance44,45. Or,
  from flow-volume loops measurements46. However,
  the fastest and easiest method to detect such
  effects is the use of a whole body plethysmograph
  with CO2 challenge47. Many airborne chemicals
  have been evaluated this way48. Some49 have
  recently suggested using minute volume (VT f).
  This is nonsense.
• The animal of choice is the guinea pig for
  any of the mentioned methods.

12

• vi) Extrapolation to Humans
• Unfortunately the results obtained in animals
  have not been systematically collected so that
  qualitative or quantitative extrapolation to
  humans can be made. At best, what we can say is
  that if a chemical is found to induce airways
  constriction in guinea pigs it will do so in
  humans.
• vii) Systems and Results
• The following pages introduce you to various
  systems used and typical results.