Improving the Efficiency of Fixed-Dose Procedures for the Assessment of Acute Oral Toxicity

Abstract

The fixed-dose procedure and the acute-toxic-class method provide alternatives to the LD₅₀ test for the classification of substances by their acute oral toxicity. This paper uses a general mathematical model to explore a wider class of fixed-dose procedures. In these procedures the number of animals included at each dose and the decision criteria regarding the next dose to be used are altered. The use of a number of measures of performance for the procedures, including the expected number of deaths caused and the probability that a substance is given an inappropriate classification, enable comparison of the procedures in this class.

It is found that misclassification is least likely for a test in which the most likely classification depends only on the LD₅₀ of the compound under investigation. Reducing the number of animals used at each dose reduces the expected number of deaths but increases the probability of misclassification. As a compromise, it is proposed that a procedure with six animals tested at each dose be used. The decision as to whether to continue at a higher or lower dose would be based on whether three or more of these animals die. Assuming that the 51 compounds from the Health and Safety Executive database are representative of those tested, such a procedure would give the correct classification for approximately 90% of compounds.