AbstractThe uptake via inhalation of a series of 1,1,1-trihaloethanes was studied using a closed ... more AbstractThe uptake via inhalation of a series of 1,1,1-trihaloethanes was studied using a closed recirculated atmosphere exposure chamber. Rats were exposed to an initial concentration of 1,1,1-trihaloethane and the rate of disappearance of chamber concentration was monitored over a period of 3 h. The in vivo metabolic rate constants for the uptake of the 1,1,1-trihaloethanes were determined using a physiologically based pharmacokinetic computer model. The uptakes for 1,1,1-trihaloethane, 1,1 -dichloro-1 -fluoroethane, 1 -chloro-1,1 -difluoro-ethane, and 1,1,1 -trilluoro-ethane were described by single first-order processes with first-order rate constants, kic, of 3.78 ± 0.02, 3.15 ± 0.11, 2.59 ± 0.02, and 1.17 ± 0.01 h−1 kg−1, respectively. The pharmacokinetic behavior of the four 1,1,1-trihaloethanes correlated well with the physicochemical characteristics; αmol (molar polarizability), calculated log P (clog P, an estimate of the octanol: water partition coefficient), and δHact (enthalpy of activation)....
Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the b... more Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the body of a toxic substance, including the possible emergence of metabolites. Traditionally, the data needed to understand those phenomena have been obtained in vivo. Currently, with a drive towards non-animal testing approaches, TK has been identified as a key element to integrate the results from in silico, in vitro and already available in vivo studies. TK is needed to estimate the range of target organ doses that can be expected from realistic human external exposure scenarios. This information is crucial for determining the dose/concentration range that should be used for in vitro testing. Vice versa, TK is necessary to convert the in vitro results, generated at tissue/cell or sub-cellular level, into dose response or potency information relating to the entire target organism, i.e. the human body (in vitro-in vivo extrapolation, IVIVE). Physiologically based toxicokinetic modelling (PBTK) is currently regarded as the most adequate approach to simulate human TK and extrapolate between in vitro and in vivo contexts. The fact that PBTK models are mechanism-based which allows them to be 'generic' to a certain extent (various extrapolations possible) has been critical for their success so far. The need for high-quality in vitro and in silico data on absorption, distribution, metabolism as well as excretion (ADME) as input for PBTK models to predict human dose-response curves is currently a bottleneck for integrative risk assessment.
The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) Strategy ... more The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) Strategy Document on Toxicokinetics (TK) outlines strategies to enable prediction of systemic toxicity by applying new approach methodologies (NAM). The central feature of the strategy focuses on using physiologically-based kinetic (PBK) modelling to integrate data generated by in vitro and in silico methods for absorption, distribution, metabolism, and excretion (ADME) in humans for predicting whole-body TK behaviour, for environmental chemicals, drugs, nano-materials, and mixtures. In order to facilitate acceptance and use of this new generation of PBK models, which do not rely on animal/human in vivo data in the regulatory domain, experts were invited by EURL ECVAM to (i) identify current challenges in the application of PBK modelling to support regulatory decision making; (ii) discuss challenges in constructing models with no in vivo kinetic data and opportunities for estimating parameter val...
An existing physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) ... more An existing physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was refined to improve the simulations of the venous blood concentrations of the primary monoester metabolite, mono-(2-propylheptyl) phthalate (MPHP). This was considered a significant deficiency that should be addressed because the primary metabolite of other high molecular weight phthalates has been associated with toxicity. The various processes that influence the concentration of DPHP and MPHP in blood were re-evaluated and modified. A few simplifications of the existing model were made, including the removal of enterohepatic recirculation (EHR) of MPHP. However, the primary development was describing the partial binding of MPHP to plasma proteins following uptake of DPHP and metabolism in the gut affording better simulation of the trends observed in the biological monitoring data. Secondly, the relationship between blood concentrations and the urinary excretion of secondary metaboli...
The kinetics of the high affinity uptake system for L-tryptophan (L-Try) have been measured over ... more The kinetics of the high affinity uptake system for L-tryptophan (L-Try) have been measured over 24 hr in cortical synaptosome preparations of rat brain. Both the Km and Vmax of the uptake process showed a statistically significant 24 hr variation. The highest Km value, 6.71 X 10(-5) M, was measured at the beginning of the light phase and the lowest value, 4.23 X 10(-5) M, 6 hr into the dark phase. Vmax was highest at the end of the dark phase (10.43 nmol/mg/5 min) and lowest (4.80 nmol/mg/5 min) 3 hr into the dark phase. In contrast, there was no variation over 24 hr in the Vmax/Km ratio. These results suggest that the high affinity uptake process serves to ensure a constant rate of L-tryptophan entry into the neuron in the face of circadian or ultradian variations in extracellular concentration of tryptophan.
A computational workflow which integrates physiologically based kinetic (PBK) modelling; global s... more A computational workflow which integrates physiologically based kinetic (PBK) modelling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC), Markov Chain Monte Carlo (MCMC) simulation and the Virtual Cell Based Assay (VCBA) for the estimation of the active, free in vitro concentration of chemical in the reaction medium was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow was designed to estimate parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for bisphenol A (BPA) and high throughput screening (HTS) in vitro concentration-response data, for estrogen and pregnane X receptor activation determined in human liver and kidney cell lines, from the ToxCast/Tox21 database. In vivo benchmark dose 10% lower confidence limits (BMDL10) for oral uptake of BPA (ng/kg BW/day) were calculated from the in vivo dose-responses and compared to the human equiva...
A computational workflow was developed to facilitate the process of quantitative to extrapolation... more A computational workflow was developed to facilitate the process of quantitative to extrapolation (QIVIVE), specifically the translation of concentration-response to dose-response relationships and subsequent derivation of a benchmark dose value (BMD). The workflow integrates physiologically based pharmacokinetic (PBPK) modeling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC) and Markov Chain Monte Carlo (MCMC) simulation. For a given set of concentration and response data the algorithm returns the posterior distribution of the corresponding , population-based dose-response values, for a given route of exposure. The novel aspect of the workflow is a rigorous statistical framework for accommodating uncertainty in both the parameters of the PBPK model (both parameter uncertainty and population variability) and in the structure of the PBPK model itself recognizing that the model is an approximation to reality. Both these sources of uncertainty propagate throu...
AbstractThe uptake via inhalation of a series of 1,1,1-trihaloethanes was studied using a closed ... more AbstractThe uptake via inhalation of a series of 1,1,1-trihaloethanes was studied using a closed recirculated atmosphere exposure chamber. Rats were exposed to an initial concentration of 1,1,1-trihaloethane and the rate of disappearance of chamber concentration was monitored over a period of 3 h. The in vivo metabolic rate constants for the uptake of the 1,1,1-trihaloethanes were determined using a physiologically based pharmacokinetic computer model. The uptakes for 1,1,1-trihaloethane, 1,1 -dichloro-1 -fluoroethane, 1 -chloro-1,1 -difluoro-ethane, and 1,1,1 -trilluoro-ethane were described by single first-order processes with first-order rate constants, kic, of 3.78 ± 0.02, 3.15 ± 0.11, 2.59 ± 0.02, and 1.17 ± 0.01 h−1 kg−1, respectively. The pharmacokinetic behavior of the four 1,1,1-trihaloethanes correlated well with the physicochemical characteristics; αmol (molar polarizability), calculated log P (clog P, an estimate of the octanol: water partition coefficient), and δHact (enthalpy of activation)....
Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the b... more Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the body of a toxic substance, including the possible emergence of metabolites. Traditionally, the data needed to understand those phenomena have been obtained in vivo. Currently, with a drive towards non-animal testing approaches, TK has been identified as a key element to integrate the results from in silico, in vitro and already available in vivo studies. TK is needed to estimate the range of target organ doses that can be expected from realistic human external exposure scenarios. This information is crucial for determining the dose/concentration range that should be used for in vitro testing. Vice versa, TK is necessary to convert the in vitro results, generated at tissue/cell or sub-cellular level, into dose response or potency information relating to the entire target organism, i.e. the human body (in vitro-in vivo extrapolation, IVIVE). Physiologically based toxicokinetic modelling (PBTK) is currently regarded as the most adequate approach to simulate human TK and extrapolate between in vitro and in vivo contexts. The fact that PBTK models are mechanism-based which allows them to be 'generic' to a certain extent (various extrapolations possible) has been critical for their success so far. The need for high-quality in vitro and in silico data on absorption, distribution, metabolism as well as excretion (ADME) as input for PBTK models to predict human dose-response curves is currently a bottleneck for integrative risk assessment.
The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) Strategy ... more The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) Strategy Document on Toxicokinetics (TK) outlines strategies to enable prediction of systemic toxicity by applying new approach methodologies (NAM). The central feature of the strategy focuses on using physiologically-based kinetic (PBK) modelling to integrate data generated by in vitro and in silico methods for absorption, distribution, metabolism, and excretion (ADME) in humans for predicting whole-body TK behaviour, for environmental chemicals, drugs, nano-materials, and mixtures. In order to facilitate acceptance and use of this new generation of PBK models, which do not rely on animal/human in vivo data in the regulatory domain, experts were invited by EURL ECVAM to (i) identify current challenges in the application of PBK modelling to support regulatory decision making; (ii) discuss challenges in constructing models with no in vivo kinetic data and opportunities for estimating parameter val...
An existing physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) ... more An existing physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was refined to improve the simulations of the venous blood concentrations of the primary monoester metabolite, mono-(2-propylheptyl) phthalate (MPHP). This was considered a significant deficiency that should be addressed because the primary metabolite of other high molecular weight phthalates has been associated with toxicity. The various processes that influence the concentration of DPHP and MPHP in blood were re-evaluated and modified. A few simplifications of the existing model were made, including the removal of enterohepatic recirculation (EHR) of MPHP. However, the primary development was describing the partial binding of MPHP to plasma proteins following uptake of DPHP and metabolism in the gut affording better simulation of the trends observed in the biological monitoring data. Secondly, the relationship between blood concentrations and the urinary excretion of secondary metaboli...
The kinetics of the high affinity uptake system for L-tryptophan (L-Try) have been measured over ... more The kinetics of the high affinity uptake system for L-tryptophan (L-Try) have been measured over 24 hr in cortical synaptosome preparations of rat brain. Both the Km and Vmax of the uptake process showed a statistically significant 24 hr variation. The highest Km value, 6.71 X 10(-5) M, was measured at the beginning of the light phase and the lowest value, 4.23 X 10(-5) M, 6 hr into the dark phase. Vmax was highest at the end of the dark phase (10.43 nmol/mg/5 min) and lowest (4.80 nmol/mg/5 min) 3 hr into the dark phase. In contrast, there was no variation over 24 hr in the Vmax/Km ratio. These results suggest that the high affinity uptake process serves to ensure a constant rate of L-tryptophan entry into the neuron in the face of circadian or ultradian variations in extracellular concentration of tryptophan.
A computational workflow which integrates physiologically based kinetic (PBK) modelling; global s... more A computational workflow which integrates physiologically based kinetic (PBK) modelling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC), Markov Chain Monte Carlo (MCMC) simulation and the Virtual Cell Based Assay (VCBA) for the estimation of the active, free in vitro concentration of chemical in the reaction medium was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow was designed to estimate parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for bisphenol A (BPA) and high throughput screening (HTS) in vitro concentration-response data, for estrogen and pregnane X receptor activation determined in human liver and kidney cell lines, from the ToxCast/Tox21 database. In vivo benchmark dose 10% lower confidence limits (BMDL10) for oral uptake of BPA (ng/kg BW/day) were calculated from the in vivo dose-responses and compared to the human equiva...
A computational workflow was developed to facilitate the process of quantitative to extrapolation... more A computational workflow was developed to facilitate the process of quantitative to extrapolation (QIVIVE), specifically the translation of concentration-response to dose-response relationships and subsequent derivation of a benchmark dose value (BMD). The workflow integrates physiologically based pharmacokinetic (PBPK) modeling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC) and Markov Chain Monte Carlo (MCMC) simulation. For a given set of concentration and response data the algorithm returns the posterior distribution of the corresponding , population-based dose-response values, for a given route of exposure. The novel aspect of the workflow is a rigorous statistical framework for accommodating uncertainty in both the parameters of the PBPK model (both parameter uncertainty and population variability) and in the structure of the PBPK model itself recognizing that the model is an approximation to reality. Both these sources of uncertainty propagate throu...
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