A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: Development and validation

Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles; Bartels, Michael; Poet, Torka S.

doi:10.1016/j.yrtph.2013.10.005

Cited by 24 publications

(12 citation statements)

References 73 publications

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“…The enhancements of the model include refining estimates of ChE inhibition rates and CYP P450 metabolism rates with measured in vivo and in vitro human and animal data. The model also includes metabolism in the intestines and other non-hepatic tissues (Price et al, 2011;Smith et al, 2014;Poet et al, 2014a,b).…”

Section: Pbpk/pd Modelmentioning

confidence: 99%

“…The modeling of these tissues also includes descriptions of reactivation and aging of these enzymes (Smith et al, 2014). The resultant model has been shown to predict the concentration of CPF in blood and TCPy in urine as well as inhibition of plasma butyryl ChE and RBC ChE in exposed individuals (Juberg et al, 2011).…”

Section: Pbpk/pd Modelmentioning

confidence: 99%

“…There are approximately 120 inputs for the PBPK/PD model used to set the BVGs (Smith et al, 2014). Many of the inputs do not vary across individuals, and other inputs vary but the model predictions are not sensitive to this variation.…”

Section: Pbpk/pd Modelmentioning

confidence: 99%

“…b Age-specific parameters are calculated using a polynomial equation, see Smith et al (2014). c The sensitivity of blood and liver volume were assessed based on the first term in a age-dependent calculation formula that predicts total volume normalized to body weight for an individual of a specific age.…”

Section: Derivation Of Bgv Values For Cpf In Blood and Tcpy In Urinementioning

confidence: 99%

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Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition

Arnold

Morriss²,

Velovitch³

et al. 2015

Regulatory Toxicology and Pharmacology

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A number of biomonitoring surveys have been performed for chlorpyrifos (CPF) and its metabolite (3,5,6-trichloro-2-pyridinol, TCPy); however, there is no available guidance on how to interpret these data in a health risk assessment context. To address this gap, Biomonitoring Guidance Values (BGVs) are developed using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model. The PBPK/PD model is used to predict the impact of age and human variability on the relationship between an early marker of cholinesterase (ChE) inhibition in the peripheral and central nervous systems [10% red blood cell (RBC) ChE inhibition] and levels of systemic biomarkers. Since the PBPK/PD model characterizes variation of sensitivity to CPF in humans, interspecies and intraspecies uncertainty factors are not needed. Derived BGVs represent the concentration of blood CPF and urinary TCPy associated with 95% of the population having less than or equal to 10% RBC ChE inhibition. Blood BGV values for CPF in adults and infants are 6100 ng/L and 4200 ng/L, respectively. Urinary TCPy BGVs for adults and infants are 2100 μg/L and 520 μg/L, respectively. The reported biomonitoring data are more than 150-fold lower than the BGVs suggesting that current US population exposures to CPF are well below levels associated with any adverse health effect.

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Section: Pbpk/pd Modelmentioning

confidence: 99%

Section: Pbpk/pd Modelmentioning

confidence: 99%

Section: Pbpk/pd Modelmentioning

confidence: 99%

Section: Derivation Of Bgv Values For Cpf In Blood and Tcpy In Urinementioning

confidence: 99%

See 2 more Smart Citations

Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition

Arnold

Morriss²,

Velovitch³

et al. 2015

Regulatory Toxicology and Pharmacology

View full text Add to dashboard Cite

show abstract

“…Timchalk et al (2006Timchalk et al ( , 2007 used these studies and others to formulate a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for developmental exposure to chlorpyrifos in rats, which supports the hypothesis that sensitivity to organophosphorus pesticides decreases with age as detoxification pathways mature. Later, Smith et al (2014) developed a PBPK/PD model for human exposure to toxic levels of chlorpyrifos (oral doses greater than 0.6 mg/kg) and concluded that six-monthold children would have higher levels of cholinesterase inhibition in their blood compared to adults.…”

Section: Introductionmentioning

confidence: 99%

Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC₅₀for whole-body (10 and 60 min) exposures

Wright¹,

Lumley²,

Lee³

et al. 2016

Drug and Chemical Toxicology

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Chemical warfare nerve agents (CWNA) inhibit acetylcholinesterase and are among the most lethal chemicals known to man. Children are predicted to be vulnerable to CWNA exposure because of their smaller body masses, higher ventilation rates and immature central nervous systems. While a handful of studies on the effects of CWNA in younger animals have been published, exposure routes relevant to battlefield or terrorist situations (i.e. inhalation for sarin) were not used. Thus, we estimated the 24 h LC for whole-body (10 and 60 min) exposure to sarin using a stagewise, adaptive dose design. Specifically, male and female Sprague-Dawley rats were exposed to a range of sarin concentrations (6.2-44.0 or 1.6-12.5 mg/m³) for either 10 or 60 min, respectively, at six different times during their development (postnatal day [PND] 7, 14, 21, 28, 42 and 70). For male and female rats, the lowest LC values were observed for PND 14 and the highest LC values for PND 28. Sex differences were observed only for PND 42 for the 10 min exposures and PND 21 and 70 for the 60 min exposures. Thus, younger rats (PND 14) were more susceptible than older rats (PND 70) to the lethal effects of whole-body exposure to sarin, while adolescent (PND 28) rats were the least susceptible and sex differences were minimal. These results underscore the importance of controlling for the age of the animal in research on the toxic effects associated with CWNA exposure.

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Pharmacokinetics and PBPK Models

Fisher

Wang²,

Duan³

et al. 2018

Comprehensive Toxicology

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A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: Development and validation

Cited by 24 publications

References 73 publications

Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition

Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition

Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC₅₀for whole-body (10 and 60 min) exposures

Pharmacokinetics and PBPK Models

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A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: Development and validation

Cited by 24 publications

References 73 publications

Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition

Derivation of human Biomonitoring Guidance Values for chlorpyrifos using a physiologically based pharmacokinetic and pharmacodynamic model of cholinesterase inhibition

Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC50for whole-body (10 and 60 min) exposures

Pharmacokinetics and PBPK Models

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Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC₅₀for whole-body (10 and 60 min) exposures