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Optimal Designs for Estimating the Effective Dose in Developmental Toxicity Experiments

机译：在发育毒性实验中估算有效剂量的优化设计

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摘要

Recent advances in risk assessment have led to the development of joint dose-response models to describe prenatal death and fetal malformation rates in developmental toxicity experiments. These models can be used to estimate the effective dose corresponding to a 5% excess risk for both these toxicological endpoints, as well as for overall toxicity. In this article, we develop optimal experimental designs for the estimation of the effective dose for developmental toxicity using joint Weibull dose-response models for prenatal death and fetal malformation. Based on an extended series of developmental studies, near-optimal designs for prenatal death, malformation, and overall toxicity were found to involve three dose groups: an unexposed control group, a high dose equal to the maximum tolerated dose, and a low dose above or comparable to the effective dose. The effect on the optimal designs of changing the number of implants and the degree of intra-litter correlation is also investigated. Although the optimal design has only three dose groups in most cases, practical considerations involving model lack of fit and estimation of the shape of the dose-response curve suggest that, in practice, suboptimal designs with more than three doses will often be preferred.
机译：风险评估的最新进展已导致开发联合剂量反应模型来描述发育毒性实验中的产前死亡和胎儿畸形率。这些模型可用于估计对应于这些毒理学终点和总体毒性的5％超额风险的有效剂量。在本文中，我们针对产前死亡和胎儿畸形的联合威布尔剂量反应模型，开发了用于评估发育毒性有效剂量的最佳实验设计。根据一系列扩展的研究，发现用于产前死亡，畸形和总体毒性的近乎最佳设计涉及三个剂量组：未暴露的对照组，高剂量等于最大耐受剂量，低剂量高于或与有效剂量相当。还研究了改变种植体数量和凋落物内相关度对优化设计的影响。尽管最佳设计在大多数情况下只有三个剂量组，但是涉及模型缺乏拟合和剂量响应曲线形状估计的实际考虑表明，在实践中，通常首选三个以上剂量的次优设计。

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