Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data,Environmental Health Perspectives

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Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2021-11-17 , DOI: 10.1289/ehp8957
Véronique Gayrard ₁ , Jessika Moreau _{1,

2} , Nicole Picard-Hagen ₁ , Virginie Helies ₃ , Philippe Marchand ₄ , Jean-Philippe Antignac ₄ , Pierre-Louis Toutain _{5,

6} , Roger Leandri _{1,

2}

Affiliation

Abstract

Background:

Although in vivo studies of internal exposure to hazardous substances have been carried out for many years, there is room for progress to improve their informative value while adhering to the four R’s: replacement, reduction, refinement, and responsibility rule.

Objectives:

The objective of the study was to illustrate how toxicokinetic (TK) study design and data analysis can be implemented under the 4R rule to plan a chronic dosage regimen for investigating TK/toxicodynamic (TD) relationships.

Methods:

The intravenous (IV) and oral serum concentrations of eight hazardous environmental contaminants including 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (pp′DDE), $lowercase beta-hexachlorocyclohexane$ ( $β -HCH$ ), hexachlorobenzene (HCB), 2,2′4,4′-tetrabromodiphenyl ether (BDE-47), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), di(2ethylhexyl)phthalate (DEHP), and bisphenol S (BPS) were obtained after mixture dosing in rabbits using a sparse sampling design. Data were comprehensively analyzed using nonlinear mixed effect (NLME) modeling.

Results:

The short persistence of BPS and of the DEHP metabolite (mono-2-ethylhexyl phthalate), reflected by their mean residence times (MRT) of a few hours, was due to their efficient clearance (CL, 3.2 and $0.47 liters per kilogram per hour$ ). The longer MRT of the other compounds (1–48 d) resulted either from their extremely low clearance (lower than $0.01 liters per kilogram per hour$ for PFOA and PFOS) or from their very large volume of distribution ( $V_{SS}$ ) ranging from 33 to $45 liters per kilogram$ . Estimates of CL, $V_{SS}$ , and bioavailability were used to compute the oral loading and daily maintenance doses required to attain a nominal steady-state serum concentration of $1 nanogram per milliliter$ . Simulations with the NLME model were applied to predict the serum concentration profile and to contrast the differential rates of accumulation in the central vs. peripheral compartments.

Conclusion:

NLME modeling of the IV and oral TK of hazardous environmental contaminants, in rabbits while fulfilling the 4R rule, was able to provide the physiological basis for interspecies extrapolation of exposure rates in a TK/TD approach to risk assessment. https://doi.org/10.1289/EHP8957

中文翻译：

八种环境污染物在兔体内的混合给药和非线性混合效应模型提高毒代动力学数据的外推值

摘要

背景：

尽管对有害物质内部暴露的体内研究已经开展了多年，但在坚持四个 R 的同时，在提高其信息价值方面仍有进步的空间：替代、减少、细化和责任规则。

目标：

该研究的目的是说明如何在 4R 规则下实施毒代动力学 (TK) 研究设计和数据分析，以规划用于研究 TK/毒代动力学 (TD) 关系的慢性给药方案。

方法：

八种有害环境污染物的静脉内 (IV) 和口服血清浓度，包括 1,1-二氯-2,2-双(对氯苯基)乙烯 (pp'DDE)， $lowercase beta-hexachlorocyclohexane$ ( $β -HCH$ )、六氯苯 (HCB)、2,2'4,4'-四溴二苯醚 (BDE-47)、全氟辛烷磺酸 (PFOS)、全氟辛酸 (PFOA)、邻苯二甲酸二(2乙基己基)酯 (DEHP) 和双酚 S (BPS) ) 是在使用稀疏抽样设计在兔子中混合给药后获得的。使用非线性混合效应 (NLME) 模型对数据进行综合分析。

结果：

BPS 和 DEHP 代谢物（邻苯二甲酸单-2-乙基己酯）的短暂持久性（通过其几小时的平均停留时间 (MRT) 反映）是由于它们的有效清除（CL，3.2 和 $0.47 liters per kilogram per hour$ ）。其他化合物的 MRT 较长（1-48 天）要么是由于它们的清除率极低（低于 $0.01 liters per kilogram per hour$ PFOA 和 PFOS）或它们的分布量非常大（ $五_{党卫军}$ ) 范围从 33 到 $45 liters per kilogram$ . CL的估计值， $五_{党卫军}$ , 和生物利用度用于计算达到标称稳态血清浓度所需的口服负荷和每日维持剂量 $1 nanogram per milliliter$ . 应用 NLME 模型的模拟来预测血清浓度曲线，并对比中央与外围隔室的不同积累率。