Bokkers Bas G H, Slob Wout
Institute for Risk Assessment Sciences (IRAS), Utrecht, The Netherlands.
Crit Rev Toxicol. 2007 Jun;37(5):355-73. doi: 10.1080/10408440701249224.
In deriving human health-based exposure limits from animal data, differences in sensitivity to a compound between animals and humans must be taken into account. These interspecies differences can be caused by differences in toxicokinetics and or toxicodynamics. Apart from that, species differ in body size, and this is usually accounted for by scaling doses to body weight (i.e., expressed as mg/kg body weight1.0/day). Adefault assessmentfactor (AF) of 10 is commonly applied to this dose metric to account for potential toxicokinetic and toxicodynamic differences. However, both proportional body weight (BW)scalingand the defaultAFas often applied are not directly based on empirical findings. Attempts have been made to derive data-based assessment factors and allometric scaling powers using various toxicological values such as no-observedadverse-effect-levels (NOAELs). In thisstudy both the NOAEL approach and the benchmark dose (BMD) approach are applied to deriveNOAEL ratios and BMD ratios from mouse and rat studies and, based on that information, toestimate an allometric scaling power and an interspecies AF. To account for interspecies differences in body size, our results confirm earlier findings that allometric body weight scaling with a power of around 0.7 is appropriate. The factor needed to rescale the dose in terms of mg/kgBWto the allometric dose scale ranges from around 1.7 (for dogs) to 10(for mice), similar to other findings. The additional factor required for taking into account interspecies toxicokinetic and toxicodynamic differences, when based on the 95th percentile of the relevant ratio distribution, would be 3.1 for a lower Confidence limit of theBMD (BMDL), and 8.3 for a NOAEL (to be applied to the allometrically scaled dose). These results indicate that the generally used defaultAFof 10 may not cover potential interspecies differences, in particular when applied to results from smaller test species. Therefore, using the default AF of 10 could lead to human exposure limits that are insufficiently protective. Further, our results show that a data-based AF that would be needed for interspecies extrapolation is smaller when the point of departure is aBMDLrather than a NOAEL. In the context of a probabilistic hazard characterization, our results indicate that the (geometric) SD of the interspecies AF distribution should be around 2.0 when the BMDL (or BMD uncertainty distribution) is used, and around 3.4 when the NOAEL is used as a point of departure for further risk assessment.
从动物数据推导基于人类健康的暴露限值时，必须考虑动物和人类对化合物敏感性的差异。这些种间差异可能由毒代动力学和/或毒效动力学的差异引起。除此之外，不同物种的体型也不同，这通常通过将剂量按体重进行换算来考虑（即表示为mg/kg体重1.0/天）。通常对该剂量指标应用默认评估因子（AF）10，以考虑潜在的毒代动力学和毒效动力学差异。然而，按比例的体重（BW）换算和经常应用的默认AF并非直接基于实证研究结果。人们已尝试使用各种毒理学值（如未观察到不良反应水平（NOAELs））来推导基于数据的评估因子和异速生长换算指数。在本研究中，NOAEL方法和基准剂量（BMD）方法均被用于从小鼠和大鼠研究中推导NOAEL比值和BMD比值，并基于该信息估计异速生长换算指数和种间AF。为了考虑种间体型差异，我们的结果证实了早期的研究发现，即幂次约为0.7的异速生长体重换算方法是合适的。将mg/kgBW剂量换算为异速生长剂量尺度所需的因子范围约为1.7（对于狗）至10（对于小鼠），与其他研究结果相似。当基于相关比值分布的第95百分位数考虑种间毒代动力学和毒效动力学差异所需的额外因子时，对于BMD的较低置信限（BMDL）为3.1，对于NOAEL（应用于异速生长换算后的剂量）为8.3。这些结果表明，通常使用的默认AF为10可能无法涵盖潜在的种间差异，特别是当应用于较小试验物种的结果时。因此，使用默认AF为10可能导致对人类的暴露限值缺乏足够的保护作用。此外，我们的结果表明，当出发点是BMDL而非NOAEL时，种间外推所需的基于数据的AF较小。在概率性危害特征描述的背景下，我们的结果表明，当使用BMDL（或BMD不确定性分布）时，种间AF分布的（几何）标准差应约为2.0，而当使用NOAEL作为进一步风险评估的出发点时，该标准差应约为3.4。
