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Reconstruction of Exposure to m-Xylene from Human Biomonitoring Data Using PBPK Modelling, Bayesian Inference, and Markov Chain Monte Carlo Simulation.

McNally K, Cotton R, Cocker J, Jones K, Bartels M, Rick D, Price P, Loizou G - J Toxicol (2012)

Bottom Line: There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals.We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene.We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures.

View Article: PubMed Central - PubMed

Affiliation: Health and Safety Laboratory, Harpur Hill, Buxton, Derbyshire SK17 9JN, UK.

ABSTRACT
There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure.

No MeSH data available.


Related in: MedlinePlus

Schematic of the PBPK model for m-xylene with a bladder compartment, to simulate fluctuations in the concentration of the main metabolite, methylhippuric acid.
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fig4: Schematic of the PBPK model for m-xylene with a bladder compartment, to simulate fluctuations in the concentration of the main metabolite, methylhippuric acid.

Mentions: A human PBPK model that includes a bladder compartment to simulate fluctuations in metabolite concentration in urine caused by micturition [30] was adapted to study the inhalation pharmacokinetics of m-xylene. Liver, adipose, richly and slowly perfused tissues, and the bladder represent the body (Figure 4). The model parameter abbreviations and point values, which are similar to previous models, are listed in Table 2 along with the distributions used in the sensitivity analysis (SA) [26, 31]. Exhalation, metabolism, and renal excretion were the routes of elimination. The concentration of unbound MHA, the main metabolite of m-xylene in the blood, assumed to be equivalent to the concentration of compound flowing through the kidney was described by the following equations:


Reconstruction of Exposure to m-Xylene from Human Biomonitoring Data Using PBPK Modelling, Bayesian Inference, and Markov Chain Monte Carlo Simulation.

McNally K, Cotton R, Cocker J, Jones K, Bartels M, Rick D, Price P, Loizou G - J Toxicol (2012)

Schematic of the PBPK model for m-xylene with a bladder compartment, to simulate fluctuations in the concentration of the main metabolite, methylhippuric acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376947&req=5

fig4: Schematic of the PBPK model for m-xylene with a bladder compartment, to simulate fluctuations in the concentration of the main metabolite, methylhippuric acid.
Mentions: A human PBPK model that includes a bladder compartment to simulate fluctuations in metabolite concentration in urine caused by micturition [30] was adapted to study the inhalation pharmacokinetics of m-xylene. Liver, adipose, richly and slowly perfused tissues, and the bladder represent the body (Figure 4). The model parameter abbreviations and point values, which are similar to previous models, are listed in Table 2 along with the distributions used in the sensitivity analysis (SA) [26, 31]. Exhalation, metabolism, and renal excretion were the routes of elimination. The concentration of unbound MHA, the main metabolite of m-xylene in the blood, assumed to be equivalent to the concentration of compound flowing through the kidney was described by the following equations:

Bottom Line: There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals.We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene.We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures.

View Article: PubMed Central - PubMed

Affiliation: Health and Safety Laboratory, Harpur Hill, Buxton, Derbyshire SK17 9JN, UK.

ABSTRACT
There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure.

No MeSH data available.


Related in: MedlinePlus