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The fixed-dose procedure and the acute-toxic-class method: a mathematical comparison

Medical and Pharmaceutical Statistics Research Unit, Department of Applied Statistics, The University of Reading, PO Box 240, Earley Gate, Reading RG6 6FN, UK

A. Whitehead

Medical and Pharmaceutical Statistics Research Unit, Department of Applied Statistics, The University of Reading, PO Box 240, Earley Gate, Reading RG6 6FN, UK

The fixed-dose procedure (FDP), proposed by the British Toxicology Society, and the acute-toxic-class (ATC) method, proposed by the German Federal Health Authority, provide alternatives to the LD₅₀ test for classify ing substances by their acute oral toxicity. This paper pre sents a mathematical model that is used to compare the two procedures in terms of their classification properties and the required numbers of animals.

It is found that the classification properties of the proce dures depend on the dose levels used, the number of ani mals tested per dose and the criteria that are used to decide whether testing should continue at a higher or lower dose. For substances with steep dose-response curves, the most likely classification is determined chiefly by the choice of the dose levels whilst the number of ani mals and continuation criteria used are increasingly important for substances with dose-response curves with a smaller slope.

The use of toxicity as a possible endpoint as in the FDP and the use of a two-stage testing procedure at each dose as in the ATC method are both found to reduce the expect ed numbers of animals required with little effect on the classification properties. On the strength of these findings it is indicated that a new procedure combining the dose levels and testing approach of the ATC method with the inclusion of toxicity as an endpoint as in the FDP would be more efficient than either the FDP or the ATC method.

Key Words: fixed-dose procedure • acute-toxic-class method • classification probabilities • acute toxicity • animal welfare

Human & Experimental Toxicology, Vol. 14, No. 12, 974-990 (1995)
DOI: 10.1177/096032719501401206


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