A comparison of ratio distributions based on the NOAEL and the benchmark approach for subchronic-to-chronic extrapolation
A comparison of ratio distributions based on the NOAEL and the benchmark approach for subchronic-to-chronic extrapolation
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DOI：
10.1093/toxsci/kfi144
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发表时间：
2005-06-01
影响因子：
3.8
通讯作者：
Slob, W
中科院分区：
文献类型：
--
作者：
Bokkers, BGH;Slob, W
得出亚慢性到慢性外推的基于数据的评估因子(AF)的一种方法是确定相同化合物的NOAEL(亚慢性)和NOAEL(慢性)之间的比率。除了使用NOAELs的比率，还可以通过亚慢性和慢性基准剂量(或临界效应剂量，CED，对于连续数据)的比率来估计分布。在这项研究中，选择了314个关于小鼠和大鼠体重和肝脏重量的剂量反应数据集，提供了亚慢性和慢性暴露后的剂量反应信息。在这些数据集中，只有68个数据集可以得出NOAEL比率，而189个数据集中可以得出CED比率。当只评估适合这两种方法的53个数据集时，CED比分布的变化(GSD[几何标准差]：2.9)小于NOAEL比分布的变化(GSD：3.3)。在对各个CED比率的估计误差进行修正后，CED分布的GSD降至2.3。NOAEL和CED分布的几何平均(GM)相似(分别为1.2和1.6)。比较基于所有68个适合得出NOAEL比率的数据集的NOAEL分布与基于适合得出CED比率的189个比率的CED分布，得到相似的GMS(分别为1.5和1.7)，但GSD显著不同(分别为5.3和2.3)。结论是，使用CED方法会导致分布范围较小。此外，较大比例的可用数据集对于告知比率分布是有用的。与目前已提出的基于NOAEL比率的分布相比，这导致了AFS的总体分布更准确、保守程度更低。
One approach to derive a data-based assessment factor (AF) for subchronic-to-chronic extrapolation is to determine ratios between the NOAEL(subchronic) and NOAEL(chronic) for the same compounds. Instead of using ratios of NOAELs, the distribution can also be estimated by ratios of subchronic and chronic Benchmark Doses (or Critical Effect Doses, CEDs, for continuous data). In this study 314 dose-response datasets on body weights and liver weights of mice and rats were selected providing dose-response information after both subchronic and chronic exposure. NOAEL ratios could be derived in only 68 of these datasets, while CED ratios could be derived in 189 datasets. When only the (53) datasets suitable for both approaches were evaluated the variation of the CED ratio distribution (GSD [geometric standard deviation]: 2.9) was smaller than the one of the NOAEL ratio distribution (GSD: 3.3). After correcting for the estimation error of the individual CED ratios the GSD of the CED distribution decreased to 2.3. The geometric means (GMs) of the NOAEL and CED distributions were similar (1.2 and 1.6, respectively). Comparing the NOAEL distribution based on all 68 datasets suitable for deriving NOAEL ratios with the CED distribution based on the 189 ratios suitable for deriving CED ratios resulted in similar GMs (1.5 and 1.7, respectively), but the GSDs differed considerably (5.3 and 2.3 respectively). It is concluded that usage of the CED approach results in less wide distributions. Furthermore, a larger fraction of available datasets is useful to inform the ratio distribution. This results in more accurate, and less conservative distributions of AFs in general compared to the distributions based on NOAEL ratios that have been proposed so far.