Improving the Efficiency of Fixed-Dose Procedures for the Assessment of Acute Oral Toxicity
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Drug Information Journal, Vol. 31, pp. 369-385, 1997 Printed in the USA. All rights reserved.
IMPROVING THE EFFICIENCY OF FIXED-DOSE PROCEDURES FOR THE ASSESSMENT OF ACUTE ORAL TOXICITY NIGEL STALLARD AND ANNEWHITEHEAD Medical and Pharmaceutical Statistics Research Unit, Department of Applied Statistics, The University of Reading, Reading, United Kingdom
The fied-dose procedure and the acute-toxic-class method provide alternatives to the LD, test for the classification of substances by their acute oral toxicity. This paper uses a general mathematical model to explore a wider class offixed-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 f o r 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 rnisclassification is least likely for a test in which the most likely classification depends only on the LDso 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. Key Words: Fixed-dose procedure; Acute-toxic-class method; Classification probabilities; LDSotest; Animal welfare
INTRODUCTION TRADITIONALLY, THE standard method for assessment of the acute oral toxicity of a compound has been the LD5,, test (1). Two been alternative methods that have developed are the fixed-dose procedure (FDP) proposed by the British Toxicology
Society (2,3) and the acute-toxic-class (ATC) method proposed by the German Federal Health Authority (4,5). In the European Community the assessment of acute oral toxicity is used mainly to place the substance under investigation into one of four categories (6). The substance is classified as “very toxic” if the estimated LD,,.,” is less than 25 mz Der kz body weight. as “toxic” if it is between 25 and 200 mg/kg, and as “harmful” if it is between 200 and 2000 mgkg. Substances with an e d mated LDSo larger than 2000 mgkg are V
Reprint address: Nigel Stallard, Medical and Pharmaceutical Statistics Research Unit, Department of Apdied Statistics. The Universitv of Readine. PO Box 240, Earley Gate, Reading RG6 6FN, United Kingdom.
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termed “unclassified.” The FDP method and ATC method aim to classify compounds directly rather than
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