使用贝叶斯分层方法估计小鼠、大鼠和非人灵长类动物中特定物种和性别的全氟烷基和多氟烷基物质(PFAS)药代动力学。
Estimation of species- and sex-specific PFAS pharmacokinetics in mice, rats, and non-human primates using a Bayesian hierarchical methodology.
作者信息
Zurlinden Todd J, Dzierlenga Michael W, Kapraun Dustin F, Ring Caroline, Bernstein Amanda S, Schlosser Paul M, Morozov Viktor
机构信息
U.S. Environmental Protection Agency, Office of Research and Development, Center for Public Health and Environmental Assessment, USA.
U.S. Environmental Protection Agency, Office of Research and Development, Center for Public Health and Environmental Assessment, USA.
出版信息
Toxicol Appl Pharmacol. 2025 Jun;499:117336. doi: 10.1016/j.taap.2025.117336. Epub 2025 Apr 8.
The carbon chain length, degree of fluorination, and functional group of per- and polyfluoroalkyl substances (PFAS) influences the bioaccumulation and half-lives of these substances in humans and laboratory animals. Pharmacokinetic (PK) studies using laboratory animals characterize the absorption, distribution, metabolism, and excretion (ADME) of a PFAS and can provide the underlying data for inter-species extrapolation to inform human pharmacokinetics. However, variations in ADME arise due to differences in protein binding and renal and hepatobiliary clearance mechanisms. In particular, sex- and species-specific differences in active transporter abundance and PFAS binding affinity challenge body weight-based extrapolation assumptions from animal models to human PK parameters. Because these protein-dependent changes in ADME do not always scale with species body weight, classic allometric scaling assumptions can fail to account for species-specific transporter-mediated clearance. In addition, study-dependent differences in pharmacokinetic modeling approaches and parameterization techniques can result in large differences among the PK parameters reported in the literature. To better quantify PFAS pharmacokinetics and characterize the underlying uncertainty, we implemented a Bayesian inference hierarchical model to estimate PFAS PK parameters for multiple species (mice, rats, and non-human primates) using numerous single-dose animal studies. Through an alternative parameterization of the one- and two-compartment models, this method improved parameter identifiability and allowed for the use of prior information on PFAS absorption rate, clearance, and volume of distribution. Using reported time-course concentration data, we estimated sex-specific clearance, volume of distribution, and half-life across mice, rats, and non-human primates using a consistent modeling methodology for eight PFAS: PFHxA, PFHxS, PFNA, PFDA, PFBS, PFBA, PFOA, and PFOS. The resulting comparison to available human data demonstrated that standard volume of distribution body-mass scaling (BW) for PFAS generally agrees with reported human values while standard assumptions for allometric scaling of clearance (BW) are not appropriate for most of the PFAS investigated in this study. In addition, we demonstrated that there may be considerable differences in clearance for PFAS in some species when comparing across different sexes and routes of exposure.
全氟和多氟烷基物质(PFAS)的碳链长度、氟化程度和官能团会影响这些物质在人类和实验动物体内的生物累积和半衰期。使用实验动物进行的药代动力学(PK)研究可表征PFAS的吸收、分布、代谢和排泄(ADME),并可为跨物种外推以了解人类药代动力学提供基础数据。然而,由于蛋白质结合以及肾脏和肝胆清除机制的差异,ADME会出现变化。特别是,主动转运蛋白丰度和PFAS结合亲和力的性别和物种特异性差异对基于体重从动物模型外推至人类PK参数的假设提出了挑战。由于这些ADME中依赖蛋白质的变化并不总是与物种体重成比例,经典的异速生长比例假设可能无法考虑物种特异性转运蛋白介导的清除。此外,药代动力学建模方法和参数化技术的研究依赖性差异可能导致文献中报道的PK参数存在很大差异。为了更好地量化PFAS药代动力学并表征潜在的不确定性,我们实施了贝叶斯推理层次模型,以使用大量单剂量动物研究来估计多种物种(小鼠、大鼠和非人类灵长类动物)的PFAS PK参数。通过对单室和双室模型进行替代参数化,该方法提高了参数可识别性,并允许使用关于PFAS吸收率、清除率和分布容积的先验信息。使用报告的时间进程浓度数据,我们使用一致的建模方法对八种PFAS(PFHxA、PFHxS、PFNA、PFDA、PFBS、PFBA、PFOA和PFOS)估计了小鼠、大鼠和非人类灵长类动物的性别特异性清除率、分布容积和半衰期。与现有人类数据的比较结果表明,PFAS的标准分布容积体重标度(BW)通常与报告的人类值一致,而清除率异速生长标度(BW)的标准假设不适用于本研究中调查的大多数PFAS。此外,我们证明,在比较不同性别和暴露途径时,某些物种中PFAS的清除率可能存在相当大的差异。