title: The fixed-dose procedure and the acute-toxic-class method: a mathematical comparison.
abstract: 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 classifying substances by their acute oral toxicity. This paper presents 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 procedures depend on the dose levels used, the number of animals 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 animals 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 expected 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.
authors.affiliation: Department of Applied Statistics, University of Reading, UK.
authors.forename: N
authors.initials: N
authors.lastname: Stallard
authors.forename: A
authors.initials: A
authors.lastname: Whitehead
mesh_terms: D000827:Animal Welfare; D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005858:Germany; D007928:Lethal Dose 50; D008722:Methods; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000145:classification*; D018675:Toxicity Tests; D006113:United Kingdom
chemical_list: D004364:Pharmaceutical Preparations