Kavlock R J, Schmid J E, Setzer R W
RTD, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Risk Anal. 1996 Jun;16(3):399-410. doi: 10.1111/j.1539-6924.1996.tb01474.x.
The benchmark dose (BMD)4 approach is emerging as replacement to determination of the No Observed Adverse Effect Level (NOAEL) in noncancer risk assessment. This possibility raises the issue as to whether current study designs for endpoints such as developmental toxicity, optimized for detecting pair wise comparisons, could be improved for the purpose of calculating BMDs. In this paper, we examine various aspects of study design (number of dose groups, dose spacing, dose placement, and sample size per dose group) on BMDs for two endpoints of developmental toxicity (the incidence of abnormalities and of reduced fetal weight). Design performance was judged by the mean-squared error (reflective of the variance and bias) of the maximum likelihood estimate (MLE) from the log-logistic model of the 5% added risk level (the likely target risk for a benchmark calculation), as well as by the length of its 95% confidence interval (the lower value of which is the (BMD). We found that of the designs evaluated, the best results were obtained when two dose levels had response rates above the background level, one of which was near the ED05, were present. This situation is more likely to occur with more, rather than fewer dose levels per experiment. In this instance, there was virtually no advantage in increasing the sample size from 10 to 20 litters per dose group. If neither of the two dose groups with response rates above the background level was near the ED05, satisfactory results were also obtained, but the BMDs tended to be more conservative (i.e., lower). If only one dose level with a response rate above the background level was present, and it was near the ED05, reasonable results for the MLE and BMD were obtained, but here we observed benefits of larger dose group sizes. The poorest results were obtained when only a single group with an elevated response rate was present, and the response rate was much greater than the ED05. The results indicate that while the benchmark dose approach is readily applicable to the standard study designs and generally observed dose-responses in developmental assays, some minor design modifications would increase the accuracy and precision of the BMD.
基准剂量（BMD）方法正在成为非癌症风险评估中确定未观察到有害作用水平（NOAEL）的替代方法。这种可能性引发了一个问题，即当前针对发育毒性等终点的研究设计（这些设计针对检测两两比较进行了优化）是否可以为计算BMD的目的而改进。在本文中，我们研究了研究设计的各个方面（剂量组数、剂量间距、剂量设置以及每个剂量组的样本量）对发育毒性两个终点（异常发生率和胎儿体重减轻率）的BMD的影响。通过来自5%额外风险水平（基准计算的可能目标风险）的对数逻辑模型的最大似然估计（MLE）的均方误差（反映方差和偏差）以及其95%置信区间的长度（其下限为BMD）来判断设计性能。我们发现，在所评估的设计中，当有两个剂量水平的反应率高于背景水平，且其中一个接近ED05时，能获得最佳结果。每个实验的剂量水平越多而非越少，这种情况越有可能发生。在这种情况下，将每个剂量组的样本量从10窝增加到20窝几乎没有优势。如果两个反应率高于背景水平的剂量组都不接近ED05，也能获得满意结果，但BMD往往更保守（即更低）。如果只有一个反应率高于背景水平的剂量水平，且它接近ED05，则MLE和BMD能得到合理结果，但在这里我们观察到更大剂量组规模的好处。当只有一个反应率升高的组且反应率远高于ED05时，得到的结果最差。结果表明，虽然基准剂量方法很容易应用于标准研究设计以及发育试验中普遍观察到的剂量反应，但一些小的设计修改将提高BMD的准确性和精确性。
