Hunt Daniel L, Li Chin-Shang
Department of Biostatistics, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
Toxicol Sci. 2006 Jul;92(1):329-34. doi: 10.1093/toxsci/kfj202. Epub 2006 Apr 19.
Observed dose-response patterns of data from several developmental toxicity experiments appear to be nonlinear and should be characterized by an appropriate model to adequately fit this observed pattern. Information from these animal studies of ambient substances that are noncarcinogenic, yet potentially toxic, to humans is used by federal protection agencies (Environmental Protection Agency, Occupational Safety and Health Administration, Food and Drug Administration) to determine safe exposure levels, such as no observed adverse effects level and benchmark dose. We have developed a flexible regression linear B-spline model for application to developmental toxicity dose-response data from animal studies of these noncarcinogens. We apply our model to data from two CD-1 mice studies of the National Toxicology Program; the observed dose-response pattern from both appears nonlinear: (1) experiment of 131 pregnant mice allocated over five exposure levels (0, 0.025, 0.05, 0.10, and 0.15% diet) of diethylhexyl phthalate and (2) experiment of 111 pregnant mice exposed to five levels (0, 62.5, 125, 250, and 500 mg/kg/day) of diethylene glycol dimethyl ether. In each study, we measure litter response as the proportion of adversely affected fetuses. Upon applying our B-spline model to the data from both studies, we predict nonlinear dose-response, with improvement over the more typical logistic dose-response model in each of the two studies.
来自多项发育毒性实验的数据所观察到的剂量反应模式似乎是非线性的，应以适当的模型进行表征，以充分拟合这种观察到的模式。联邦保护机构（环境保护局、职业安全与健康管理局、食品药品管理局）利用这些关于对人类无致癌性但有潜在毒性的环境物质的动物研究信息来确定安全暴露水平，如未观察到不良反应水平和基准剂量。我们开发了一种灵活的回归线性B样条模型，用于应用于这些非致癌物动物研究的发育毒性剂量反应数据。我们将我们的模型应用于国家毒理学计划的两项CD - 1小鼠研究的数据；两项研究中观察到的剂量反应模式似乎都是非线性的：（1）131只怀孕小鼠分配到邻苯二甲酸二乙基己酯的五个暴露水平（0、0.025、0.05、0.10和0.15%饮食）的实验，以及（2）111只怀孕小鼠暴露于五个水平（0、62.5、125、250和500 mg/kg/天）的二甘醇二甲醚的实验。在每项研究中，我们将窝仔反应测量为受不利影响胎儿的比例。将我们的B样条模型应用于两项研究的数据后，我们预测了非线性剂量反应，在两项研究中的每一项中都比更典型的逻辑剂量反应模型有所改进。
