Allen B C, Strong P L, Price C J, Hubbard S A, Daston G P
K. S. Crump Division, ICF Kaiser International, Morrisville, North Carolina, USA.
Fundam Appl Toxicol. 1996 Aug;32(2):194-204. doi: 10.1006/faat.1996.0122.
Developmental toxicity risk assessment has typically relied on the estimation of reference doses or reference concentrations based on the use of no-observed-adverse-effect levels (NOAELs) divided by uncertainty factors. The benchmark dose (BMD) approach has been proposed as an alternative basis for reference value calculations. In this analysis of the developmental toxicity observed in rats exposed to boric acid in their diet, BMD analyses have been conducted using two existing studies. By considering various end points (rib XIII effects, variations of the first lumbar rib, and fetal weight changes) and various modeling approaches for those end points, the best approach for incorporating all of the information available from those studies could be determined. Particular emphasis has been placed on methods for combining data across studies and for combining potentially related effects (on rib XIII and on the first lumbar rib). The issues of study and end point selection are ones that will arise frequently in the process of estimating reference values. This example of boric acid suggests that the BMD approach provides a reasonable basis for appropriately comparing and combining study data, as opposed to ad hoc combinations of study results. Moreover, it is shown that the BMD approach can be used with combinations of end points considered to differ in severity. In this case, the preferred approach involved combining the data from the two studies, which were similarly designed and were conducted in the same laboratory, to calculate BMDs that were more accurate and more precise than those that could be derived from either study alone. It was determined that decreased fetal body weight provided the best basis for BMD calculations; BMDs calculated for fetal body weight changes were less than those for all other relevant end points. The appropriate BMD to use as the basis for boric acid reference dose calculation appears to be 59 mg/kg/day, which is very similar to the NOAEL observed in the second of the two studies (55 mg/kg/day). Although the first study failed to establish a NOAEL, the BMD approach could have been applied to that study, thereby avoiding the need for a repeat study. Similar BMD results were obtained in both studies.
发育毒性风险评估通常依赖于基于未观察到不良效应水平（NOAELs）除以不确定性因子来估算参考剂量或参考浓度。基准剂量（BMD）方法已被提议作为参考值计算的替代基础。在对饮食中接触硼酸的大鼠所观察到的发育毒性进行的本分析中，已使用两项现有研究进行了BMD分析。通过考虑各种终点（第XIII肋骨效应、第一腰椎肋骨变异和胎儿体重变化）以及针对这些终点的各种建模方法，可以确定纳入这些研究中所有可用信息的最佳方法。特别强调了跨研究合并数据以及合并潜在相关效应（对第XIII肋骨和第一腰椎肋骨的效应）的方法。研究和终点选择问题是在估算参考值过程中经常会出现的问题。硼酸的这个例子表明，与临时合并研究结果相反，BMD方法为适当地比较和合并研究数据提供了合理依据。此外，结果表明BMD方法可用于被认为严重程度不同的终点组合。在这种情况下，首选方法是合并两项设计相似且在同一实验室进行的研究的数据，以计算比单独从任何一项研究得出的更准确、更精确的BMDs。已确定胎儿体重下降为BMD计算提供了最佳依据；针对胎儿体重变化计算的BMDs低于所有其他相关终点的BMDs。用作硼酸参考剂量计算基础的合适BMD似乎为59毫克/千克/天，这与两项研究中的第二项所观察到的NOAEL（55毫克/千克/天）非常相似。尽管第一项研究未能确定NOAEL，但BMD方法本可应用于该研究，从而避免进行重复研究。两项研究都获得了相似的BMD结果。
