Pharmacologic Considerations in the Design of Toxicology Experiments

During discussions held near the beginning of the 1960s on drug safety and effectiveness, Louis Goodman stated that effectiveness was achieved when the agent accomplished the effect for which it was administered, and safety was experienced when no unexpected responses occurred. While proving safety by removal of unexpected responses seems simple, forming the data base which eliminates unexpected responses has proven to be an all-consuming task for the toxicologist. Basically, the safe use of a substance does depend on the user having a thorough knowledge of its actions. An excellent example of this statement is exhibited by a review of the use of sodium pentothal over time. This agent was introduced in the 1930s. By the time the United States entered World War I1 the drug was moderately successful. In the mass casualty situations at Pearl Harbor and in North Africa use of sodium pentothal resulted in the drug being branded as "the kiss of death" [l-31. Blood loss and shock were two conditions where little information existed to support the safe use of the agent. When dose/ response studies supported the reduction of the dose and the rate of administration under these conditions, the safe use of sodium pentothal was reestablished. In the early 1950s wide use of the drug was accompanied by another series of adverse reactions. With multiple injection in a single patient, hypotension, respiratory collapse, and death occurred. These effects could be related to the then held belief that sodium pentothal was a "short-acting" barbiturate because it was