Dataset Information

Estimating Methylmercury Intake for the General Population of South Korea Using Physiologically Based Pharmacokinetic Modeling.

ABSTRACT: The Korean National Environmental Health Survey (KoNEHS 2009-2011) tracks levels of environmental pollutants in biological samples from the adult Korean population (age 19-88). Recent survey results for blood mercury (Hg) suggest some exceedance above existing blood Hg reference levels. Because total blood Hg represents both organic and inorganic forms, and methylmercury (MeHg) has been specifically linked to several adverse health outcomes, a need exists to quantify MeHg intake for this population. Gender, age, and frequency of fish consumption were first identified as important predictors of KoNEHS blood Hg levels using generalized linear models. Stratified distributions of total blood Hg were then used to estimate distributions of blood MeHg using fractions of MeHg to total Hg from the literature. Next, a published physiologically based pharmacokinetic (PBPK) model was used to predict distributions of blood MeHg as a function of MeHg intake; ratios of MeHg intake to model-predicted blood MeHg were then combined with KoNEHS-based blood MeHg values to produce MeHg intake estimates. These intake estimates were ultimately compared with the Reference Dose (RfD) for MeHg (0.1 µg/kg/day) and reported as margin of exposure (MOE) estimates for specific KoNEHS subgroups. The derived MOEs across all subgroups, based on estimated geometric mean intake, ranged from 1.6 to 4.1. These results suggest MeHg exposures approaching the RfD for several subgroups of the Korean population, and not just for specific subgroups (eg, those who eat fish very frequently).

SUBMITTER: Lee S

PROVIDER: S-EPMC6145084 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Estimating Methylmercury Intake for the General Population of South Korea Using Physiologically Based Pharmacokinetic Modeling.

Lee Seungho S Tan Yu-Mei YM Phillips Martin B MB Sobus Jon R JR Kim Sungkyoon S

Toxicological sciences : an official journal of the Society of Toxicology 20170901 1

The Korean National Environmental Health Survey (KoNEHS 2009-2011) tracks levels of environmental pollutants in biological samples from the adult Korean population (age 19-88). Recent survey results for blood mercury (Hg) suggest some exceedance above existing blood Hg reference levels. Because total blood Hg represents both organic and inorganic forms, and methylmercury (MeHg) has been specifically linked to several adverse health outcomes, a need exists to quantify MeHg intake for this populat ...[more]

PMID: 28903490

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Project description:Background and objectiveWhile one in five children in the USA are now obese, and more than three-quarters receive at least one drug during childhood, there is limited dosing guidance for this vulnerable patient population. Physiologically based pharmacokinetic modeling can bridge the gap in the understanding of how pharmacokinetics, including drug distribution and clearance, changes with obesity by incorporating known obesity-related physiological changes in children. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity.MethodsTo enable physiologically based pharmacokinetic modeling, a virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The virtual population accounts for key obesity-related changes in physiology relevant to pharmacokinetics, including increased body size, body composition, organ size and blood flow, plasma protein concentrations, and glomerular filtration rate. The virtual population was then used to predict the pharmacokinetics of clindamycin and trimethoprim/sulfamethoxazole in children with obesity using previously developed physiologically based pharmacokinetic models.ResultsModel simulations predicted observed concentrations well, with an overall average fold error of 1.09, 1.24, and 1.53 for clindamycin, trimethoprim, and sulfamethoxazole, respectively. Relative to children without obesity, children with obesity experienced decreased clindamycin and trimethoprim/sulfamethoxazole weight-normalized clearance and volume of distribution, and higher absolute doses under recommended pediatric weight-based dosing regimens.ConclusionsModel simulations support current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution.

Project description:BackgroundModeling of pharmacokinetic parameters and pharmacodynamic actions requires knowledge of the arterial blood concentration. In most cases, experimental measurements are only available for a peripheral vein (usually antecubital) whose concentration may differ significantly from both arterial and central vein concentration.MethodsA physiologically based pharmacokinetic (PBPK) model for the tissues drained by the antecubital vein (referred to as "arm") is developed. It is assumed that the "arm" is composed of tissues with identical properties (partition coefficient, blood flow/gm) as the whole body tissues plus a new "tissue" representing skin arteriovenous shunts. The antecubital vein concentration depends on the following parameters: the fraction of "arm" blood flow contributed by muscle, skin, adipose, connective tissue and arteriovenous shunts, and the flow per gram of the arteriovenous shunt. The value of these parameters was investigated using simultaneous experimental measurements of arterial and antecubital concentrations for eight solutes: ethanol, thiopental, 99Tcm-diethylene triamine pentaacetate (DTPA), ketamine, D2O, acetone, methylene chloride and toluene. A new procedure is described that can be used to determine the arterial concentration for an arbitrary solute by deconvolution of the antecubital concentration. These procedures are implemented in PKQuest, a general PBPK program that is freely distributed http://www.pkquest.com.ResultsOne set of "standard arm" parameters provides an adequate description of the arterial/antecubital vein concentration for ethanol, DTPA, thiopental and ketamine. A significantly different set of "arm" parameters was required to describe the data for D2O, acetone, methylene chloride and toluene - probably because the "arm" is in a different physiological state.ConclusionsUsing the set of "standard arm" parameters, the antecubital vein concentration can be used to determine the whole body PBPK model parameters for an arbitrary solute without any additional adjustable parameters. Also, the antecubital vein concentration can be used to estimate the arterial concentration for an arbitrary input for solutes for which no arterial concentration data is available.

Dataset Information

Estimating Methylmercury Intake for the General Population of South Korea Using Physiologically Based Pharmacokinetic Modeling.

Publications

Estimating Methylmercury Intake for the General Population of South Korea Using Physiologically Based Pharmacokinetic Modeling.

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