McLanahan Eva D, White Paul, Flowers Lynn, Schlosser Paul M
U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, NC, USA.
Risk Anal. 2014 Feb;34(2):356-66. doi: 10.1111/risa.12101. Epub 2013 Jul 31.
Physiologically-based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well-defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium-iodide symporter (NIS). In this analysis, a six-step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer-reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near-term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.
基于生理学的药代动力学（PBPK）模型经常被提交给或被美国环境保护局（U.S. EPA）和有毒物质与疾病登记署等机构选用，以供在人类健康风险评估（HHRA）中考虑应用。最近，美国环境保护局评估了高氯酸盐和放射性碘的人体PBPK模型，以评估其估算不同人群和生命阶段中高氯酸盐对甲状腺放射性碘摄取抑制的相对敏感性的能力。环境污染物高氯酸盐最明确的作用方式是通过钠-碘同向转运体（NIS）竞争性抑制甲状腺碘摄取。在该分析中，遵循了PBPK模型评估的六步框架，经过一些修改后，确定这些模型适用于HHRA，以评估人类生命阶段之间的相对敏感性。通过比较PBPK模型预测的不同生命阶段高氯酸盐对甲状腺放射性碘摄取（RAIU）的抑制百分比来确定对高氯酸盐的相对敏感性。有限的敏感性分析表明，描述高氯酸盐和碘尿排泄的模型参数在预测RAIU抑制方面尤为重要；因此，评估了同行评审文献中一系列生物学上合理的值。使用更新后的PBPK模型，预测对RAIU抑制最敏感的是近期胎儿（妊娠40周），与平均成年人和其他生命阶段相比；然而，当考虑暴露因素时，发现新生儿是在高氯酸盐风险评估中需要进一步评估和考虑的人群。
