AN APPLICATION OF THE DOSIMETRIC METHOD FOR BIOLOGICALLY ASSAYING INHALED SUBSTANCES

The Determination of the Retained Median Lethal Dose, Percentage Retention, AND Respiratory Respones In Dogs Exposed To Different Concentrations of Phosgene

¹ Toxicology Section, Medical Division, Edgewood Arsenal, Maryland

1. The theoretical basis for biologically assaying inhaled materials in terms of retained dose rather than concentration-time products was discussed.

2. The methods and procedures for determining the retained dose of an inhaled substance and for calculating the acutal percentage of agent retained after inhalation were presented.

3. The principles and application of the dosimetric method were illustrated by experiments on 3 groups of 30 unanesthetized dogs in which the median lethal dose, percentage retention of inhaled agent, and respiratory changes during dosimetric exposure to 3 different concentrations of phosgene were determined.

4. The retained median lethal doses of phosgene for dogs exposed to phosgene at mean contact concentrations of 1.38, 3.45, and 6.90 mgm./l. were as follows: 1.31 mgm./kgm. (S.E. = 0.097 mgm./kgm.), 0.98 mgm./kgm. (S.E. = 0.115 mgm./kgm.), and 0.80 mgm./kgm. (S.E. = 0.135 mgm./kgm.), respectively. The increase in toxicity when the phosgene concentration was increased from 1.38 mgm./l. to 6.90 mgm./l. is statistically significant (``t'' = 3.1) and requires further experimental analysis.

5. The mean percentage of inhaled phosgene retained by the 90 dogs was 74.0% (Std. Dev. = ±12.1%; S.E. = ±1.3%). In this series no significant correlation could be made between percentage retention and tidal-air depth, or respiratory minute volume, or concentration of phosgene inhaled.

6. During the first two minutes of exposure, all animals exhibited respiratory inhibition which varied considerably in different individuals, was greatest at the highest concentrations, and was manifested by a brief period of breath-holding followed by a longer period of shallow, slow breathing. By the third minute, the respiratory minute volume was equal to or slightly greater than normal, probably as a result of hypercapnia, anoxia, and accommodation to the irritant vapors.

7. Wide discrepancies were demonstrated between concentration-time products (Ct's) and the actual retained dose, particularly in the animals exhibiting the greatest respiratory inhibition during exposure. As exposure time was increased, however, there was a somewhat more uniform relation between Ct and retained dose.

8. The experimental data reported are considered to establish the validity of biologically assessing inhaled substances in terms of retained dose rather than Ct exposures. The technique of dosimetric exposure should permit re-evaluation of certain toxicological and therapeutic aspects of poisoning by inhaled noxious agents.