Whitehead Anne, Stallard Nigel
Medical and Pharmaceutical Statistics (MPS) Research Unit, The University of Reading, P.O. Box 240, Earley Gate, Reading, Berkshire RG6 6FN, UK.
Altern Lab Anim. 2004 Sep;32 Suppl 2:73-80. doi: 10.1177/026119290403202s15.
The conventional method for assessing acute oral toxicity (OECD Test Guideline 401) was designed to identify the median lethal dose (LD50), using the death of animals as an endpoint. Introduced as an alternative method (OECD Test Guideline 420), the Fixed Dose Procedure (FDP) relies on the observation of clear signs of toxicity, uses fewer animals and causes less suffering. More recently, the Acute Toxic Class method and the Up-and-Down Procedure have also been adopted as OECD test guidelines. Both of these methods also use fewer animals than the conventional method, although they still use death as an endpoint. Each of the three new methods incorporates a sequential dosing procedure, which results in increased efficiency. In 1999, with a view to replacing OECD Test Guideline 401, the OECD requested that the three new test guidelines be updated. This was to bring them in line with the regulatory needs of all OECD Member Countries, provide further reductions in the number of animals used, and introduce refinements to reduce the pain and distress experienced by the animals. This paper describes a statistical modelling approach for the evaluation of acute oral toxicity tests, by using the revised FDP for illustration. Opportunities for further design improvements are discussed.
评估急性经口毒性的传统方法（经合组织测试指南401）旨在确定半数致死剂量（LD50），以动物死亡作为终点。作为一种替代方法（经合组织测试指南420）引入的固定剂量法（FDP），依靠对明显毒性迹象的观察，使用的动物数量更少，造成的痛苦也更小。最近，急性毒性分级法和上下法也已被采纳为经合组织测试指南。这两种方法使用的动物数量也都比传统方法少，尽管它们仍以死亡作为终点。这三种新方法都采用了序贯给药程序，从而提高了效率。1999年，为了取代经合组织测试指南401，经合组织要求对这三项新测试指南进行更新。这是为了使其符合所有经合组织成员国的监管需求，进一步减少所用动物的数量，并进行改进以减轻动物所经历的疼痛和痛苦。本文以修订后的固定剂量法为例，描述了一种用于评估急性经口毒性试验的统计建模方法。还讨论了进一步改进设计的机会。
