Krewski D, Zhu Y
Health Protection Branch, Health and Welfare Canada, Ottawa, Ontario.
Risk Anal. 1994 Aug;14(4):613-27. doi: 10.1111/j.1539-6924.1994.tb00275.x.
Reproductive and developmental anomalies induced by toxic chemicals may be identified using laboratory experiments with small mammalian species such as rats, mice, and rabbits. In this paper, dose-response models for correlated multinomial data arising in studies of developmental toxicity are discussed. These models provide a joint characterization of dose-response relationships for both embryolethality and teratogenicity. Generalized estimating equations are used for model fitting, incorporating overdispersion relative to the multinomial variation due to correlation among littermates. The fitted dose-response models are used to estimate benchmark doses in a series of experiments conducted by the U.S. National Toxicology Program. Joint analysis of prenatal death and fetal malformation using an extended Dirichlet-trinomial covariance function to characterize overdispersion appears to have statistical and computational advantages over separate analysis of these two end points. Benchmark doses based on overall toxicity are below the minimum of those for prenatal death and fetal malformation and may, thus, be preferred for risk assessment purposes.
有毒化学物质引起的生殖和发育异常可通过对大鼠、小鼠和兔子等小型哺乳动物进行实验室实验来识别。本文讨论了发育毒性研究中出现的相关多项数据的剂量反应模型。这些模型提供了胚胎致死率和致畸性剂量反应关系的联合表征。广义估计方程用于模型拟合，纳入了由于同窝幼仔间相关性导致的相对于多项变异的过度离散。拟合的剂量反应模型用于估计美国国家毒理学计划进行的一系列实验中的基准剂量。使用扩展的狄利克雷 - 三项式协方差函数来表征过度离散对产前死亡和胎儿畸形进行联合分析，相对于分别分析这两个终点似乎具有统计和计算优势。基于总体毒性的基准剂量低于产前死亡和胎儿畸形的基准剂量最小值，因此可能更适合用于风险评估目的。
