Evaluation of Age-Related Pyrethroid Pharmacokinetic Differences in Rats: Physiologically-Based Pharmacokinetic Model Development Using In Vitro Data and In Vitro to In Vivo Extrapolation

Song, Gina; Moreau, Marjory; Efremenko, Alina; Lake, Brian G.; Wu, Huali; Bruckner, James V.; White, Catherine A.; Osimitz, Thomas G.; Creek, Moire R.; Hinderliter, Paul M.; Clewell, Harvey J.; Yoon, Miyoung

doi:10.1093/toxsci/kfz042

Cited by 19 publications

(24 citation statements)

References 50 publications

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“…The rat external PODs of 1.49, 3.13, 0.65, 6.0, 0.64, 44.4, and 1.17 mg/kg BW for deltamethrin, bifenthrin, esfenvalerate, cyphenothrin, cyhalothrin, permethrin ( cis - and trans -permethrin), and cyfluthrin, respectively were translated into brain C max using the rat PBPK model from Song et al (2019) . The estimated internal exposure PODs (brain C max ) were 28.3, 219.8, 7.3, 67.6, 17.4, 1371.8, 279.9, and 30.6 ng/g for deltamethrin, bifenthrin, esfenvalerate, cyphenothrin, cyhalothrin, cis -permethrin, trans -permethrin, and cyfluthrin, respectively ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…The total intrinsic clearance of the 8 pyrethroids (deltamethrin, cis -permethrin, trans -permethrin, esfenvalerate, bifenthrin, cyphenothrin, cyhalothrin, and cyfluthrin) were assessed in rat and human liver microsomes and cytosol in vitro and scaled to in vivo CL int . All the explanations and calculations can be find in Song et al (2019) and Mallick et al (2020) .…”

Section: Discussionmentioning

confidence: 99%

“…The current model can simulate pyrethroid kinetics through oral and inhalation in single or multiple daily exposure scenarios and incorporates age-dependent human physiology, as well as maturation profiles of pyrethroid metabolism mediated by carboxylesterases and cytochrome P450 enzymes in liver. Key assumptions of this human model’s structure and parameters are based on those evaluated in the rat model ( Song et al , 2019 ). All information relative to human model structure and parameterization as well as sensitivity analysis can be found in Mallick et al (2020) .…”

Section: Methodsmentioning

confidence: 99%

“…These PODs were used in the rat PBPK model from Song et al (2019) to estimate the maximal concentration ( C max ) at the target tissue (brain) in rat for each pyrethroid. The rat pyrethroids model was run with a daily dose of 1.5, 44.4, 3.1, 0.7, 1.2, 0.6, and 6.0 mg/kg BW for deltamethrin, permethrin ( cis -/ trans -permethrin), bifenthrin, esfenvalerate, cyfluthrin, cyhalothrin, and cyphenothrin, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids

Mallick¹,

Song²,

Efremenko³

et al. 2020

Toxicological Sciences

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids

Mallick¹,

Song²,

Efremenko³

et al. 2020

Toxicological Sciences

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“…It was necessary to estimate the free fraction of each of these chemicals in plasma from kinetic data to obtain the best fits for monkeys and humans. The K d and B max values obtained in the current study for DLM, CIS, and TRANS were used to calculate the free fraction of each isomer for PBPK modeling of the pyrethroids in maturing rats (Song et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Plasma Protein and Lipoprotein Binding ofCis- andTrans-Permethrin and Deltamethrin in Adult Humans and Rats

Sethi¹,

Bruckner²,

Mortuza³

et al. 2019

Drug Metab Dispos

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The majority of residents of the United States, Canada, and Europe are exposed to pyrethroids, the most commonly used class of insecticides. Surprisingly little is known about key aspects of their pharmacokinetics, including their mode of transport in the systemic circulation. This study tested the hypothesis that pyrethroids are transported by both plasma lipoproteins and proteins, similarly to other highly lipophilic environmental contaminants. Other aims were to characterize the binding of representative type I and II pyrethroids, and to compare their binding to rat versus human plasma. Binding of 14 C-labeled cis-permethrin (CIS), trans-permethrin (TRANS) and deltamethrin (DLM) to proteins and lipoproteins was measured by sequential extraction of spiked plasma with isooctane, 2-octanol, and acetonitrile. Binding of DLM, CIS, and TRANS to plasma proteins and lipoproteins was linear from 250 to 750 nM; concentrations present in the plasma of orally dosed rats. Binding of DLM to high-density lipoprotein was twice that to low-density lipoprotein. Binding of DLM, CIS, and TRANS was ∼2-fold greater to proteins than to lipoproteins of rat and human plasma; albumin was primarily responsible for protein binding. Higher total binding of each pyrethroid to human (∼90%) than to rat (∼80%) plasma resulted from higher protein binding in human plasma. This was attributable in part to the higher albumin/protein content of human plasma. Rat albumin exhibited lower pyrethroid binding capacity than did human albumin. The results of this investigation indicate that albumin and lipoproteins play a major role in binding and transport of pyrethroids in the systemic circulation of both rats and humans.

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Neurotoxicology of pyrethroid insecticides

Soderlund

2020

Advances in Neurotoxicology

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Evaluation of Age-Related Pyrethroid Pharmacokinetic Differences in Rats: Physiologically-Based Pharmacokinetic Model Development Using In Vitro Data and In Vitro to In Vivo Extrapolation

Cited by 19 publications

References 50 publications

Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids

Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids

Plasma Protein and Lipoprotein Binding ofCis- andTrans-Permethrin and Deltamethrin in Adult Humans and Rats

Neurotoxicology of pyrethroid insecticides

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