EFFECTS ON THE RESPIRATORY TRACT. Yves Alarie, Ph.D Professor Emeritus U niversity of Pittsburgh,USA. A. BRIEF LOOK AT ANATOMY AND PHYSIOLOGY. B. ACUTE EFFECTS
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
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
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.
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.
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).
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.
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.