Chapter 9 - Systemic Acute Toxicity Testing

Abstract

This chapter reviews systemic acute toxicity testing. In concise terms, lethality testing is single-end point testing with death as the single endpoint. Acute systemic toxicity testing is largely descriptive in nature. Acute toxicity tests are generally performed with a definite sequence, considering the following parameters: biological, safety, government regulations, and other. This chapter illustrates the use of toxicity screens in commercial compound development and the design and conduct of a general toxicity screen. A rat toxicity screen, described by Fowler and colleagues in 1979, comprises several features, which make this design too complicated, time-consuming, and expensive to run as an initial screen. In 1987, Hazelette and colleagues described a rather novel pyramiding dosage screen that they term rising dose tolerance (RDT) study, by illustrating a line chart for the design and conduct of the Hazelette style RDT study for acute systemic toxicity study. With regard to specific toxicity screening, behavioral toxicity screening is an area currently generating a great deal of interest. Moreover, this chapter stresses that endpoints other than death are also used for quality assurance testing. In fact, many of these tests are mandated by inclusion in the pharmacopias of several Western countries. Routes are also discussed in this chapter keeping the design consideration in view. Finally, this chapter concludes on acute mechanistic studies stating that in the clinical situation, it is more often the case that an acute effect will be overlayed on a chronic effect.