Reducing animal numbers in the fixed-dose procedure

The fixed-dose procedure (FDP) was proposed by the British Toxicology Society (1984) as an alternative to assessment of acute oral toxicity via estimation of the LD50. The procedure is incorporated in OECD guidelines on acute oral toxicity testing. Whitehead and Curnow (1992) used a mathematical model to describe the statistical properties of the FDP. This paper uses a simplified model to investigate further the procedure. In particular the effects of altering the number of animals included at each stage in the procedure are evaluated. It is shown that a reduction in the number of animals tested makes little difference to the toxic classification of a substance with a steep dose-response curve, but has increasing effect as the dose-response curve becomes shallower. The simplified model also shows that in the proposed procedure the most likely classification depends on the LD of the substance tested. Changing the number of animals tested results in the most likely classification depending on other LD values. The effect of additional variation is also considered. Such variation might arise from within-laboratory differences. Although this increases the range of substances for which misclassification is likely, the increase is not much affected by the number of animals tested.