EFFECTS ON THE RESPIRATORY TRACT

1. EFFECTS ON THE RESPIRATORY TRACT YvesAlarie, 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, β-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.