ScitoVation, LLC, Durham, North Carolina 27713.
Moire Creek Toxicology Consulting Services, Lincoln, California 95648.
Toxicol Sci. 2020 Aug 1;176(2):460-469. doi: 10.1093/toxsci/kfaa070.
The assessment of potentially sensitive populations is an important application of risk assessment. To address the concern for age-related sensitivity to pyrethroid insecticides, life-stage physiologically based pharmacokinetic (PBPK) modeling supported by in vitro to in vivo extrapolation was conducted to predict age-dependent changes in target tissue exposure to 8 pyrethroids. The purpose of this age-dependent dosimetry was to calculate a Data-derived Extrapolation Factor (DDEF) to address age-related pharmacokinetic differences for pyrethroids in humans. We developed a generic human PBPK model for pyrethroids based on our previously published rat model that was developed with in vivo rat data. The results demonstrated that the age-related differences in internal exposure to pyrethroids in the brain are largely determined by the differences in metabolic capacity and in physiology for pyrethroids between children and adults. The most important conclusion from our research is that, given an identical external exposure, the internal (target tissue) concentration is equal or lower in children than in adults in response to the same level of exposure to a pyrethroid. Our results show that, based on the use of the life-stage PBPK models with 8 pyrethroids, DDEF values are essentially close to 1, resulting in a DDEF for age-related pharmacokinetic differences of 1. For risk assessment purposes, this indicates that no additional adjustment factor is necessary to account for age-related pharmacokinetic differences for these pyrethroids.
对潜在敏感人群的评估是风险评估的一个重要应用。为了解决与年龄相关的对拟除虫菊酯类杀虫剂敏感性的问题，进行了基于生理学的阶段式（PBPK）建模，通过体外到体内的外推法，预测 8 种拟除虫菊酯在目标组织中的暴露量随年龄的变化。这种与年龄相关的剂量学目的是计算数据衍生外推因子（DDEF），以解决人类拟除虫菊酯类的年龄相关药代动力学差异。我们基于之前发表的大鼠模型，开发了一种通用的人类拟除虫菊酯 PBPK 模型，该模型是使用大鼠体内数据开发的。结果表明，大脑中拟除虫菊酯的内暴露随年龄的差异主要取决于儿童和成人之间代谢能力和拟除虫菊酯生理学方面的差异。我们研究的最重要结论是，对于相同的外部暴露，儿童体内（靶组织）浓度与成人相同或更低，因为接触到相同水平的拟除虫菊酯。我们的研究结果表明，基于使用 8 种拟除虫菊酯的生命阶段 PBPK 模型，DDEF 值基本上接近 1，从而导致年龄相关药代动力学差异的 DDEF 值为 1。对于风险评估目的，这表明对于这些拟除虫菊酯，不需要额外的调整因子来考虑年龄相关的药代动力学差异。
