EFFECT OF pH AND INCUBATION UPON IMMEDIATE LETHAL TOXICITY OF NITROGEN MUSTARD

¹ Children's Cancer Research Foundation, the Division of Laboratories and Research of the Children's Hospital, and the Department of Biological Chemistry, Harvard Medical School, Boston, Massachusetts

The pH of a freshly prepared solution of nitrogen mustard was found to have a pronounced effect upon the immediate lethal toxicity in mice at dose levels which affect the central nervous system and lead to death within 8 hours after injection of the agent. The influence of pH appeared to be dual. With solutions injected subcutaneously within 1 minute of mixing, survival times were shorter at pH 7.8 than at pH 1.8 to 2.0. As solutions at pH 5.0 and above were allowed to age, there was a further decrease in the survival time, which was related to the chemical transformation to cyclic derivatives in vitro. No change in toxicity or chemical transformation was seen with solutions at pH 2.0 aged up to 48 hours.

The route of administration had an important influence upon immediate lethal toxicity of nitrogen mustard as determined by the time of death. Death was markedly delayed by intraperitoneal injection, and accelerated by intravenous injection, as compared to subcutaneous administration.

Intravenous administration of HN2 produced coma within 10 seconds. In animals receiving HN2 at pH 2.0, the immediate coma lasted only 30 to 45 seconds, was followed by brief recovery and then, within minutes, by neurological signs and death. In animals receiving the same dose at pH 7.3, coma was usually irreversible. The speed of onset of the instantaneous coma, and its reversibility with solutions at pH 2.0 would seem to indicate that it was not an effect of an alkylation process, since it occurred before the mustard could have cyclized to its reactive form.