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IndusChemFate - a generic PBPK model

Submitted by Christa Cornelis on Tue, 2010-11-30 10:02
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IndusChemFate is a generic physiologically based pharmacokinetic (PBPK) model to estimate blood and urine concentrations of multiple chemicals. It is developed to predict exposure in workers and consumers, allowing for a constant 1-day exposure pattern. The IndusChemFate model considers inhalation, dermal and oral exposure. Dermal exposure considers gaseous uptake and liquid uptake by the skin.


The model is designed to be used as a screening model providing order of magnitude estimates. It uses Quantitative Structure Activity Relationships (QSPR) to estimate blood:air and tissue:blood partitioning. The model allows for metabolism in every organ, using Michaelis-Menten kinetics. Up to 4 subsequent metabolites can be simulated.

Model description
Purpose: 

IndusChemFate is a generic physiologically based pharmacokinetic model that allows the time-dependent simulation of blood and urine levels of multiple organic chemicals. It provides an order of magnitude estimate of exposure, using QSPR relationships to predict blood:air and tissue:blood partitioning.

Boundaries: 

Field: PBPK


Temporal coverage and resolution: IndusChemFate allows to create an exposure pattern for 1 day that can be repeated for 5 consecutive days. Start and end of the observation period can be specified by the user. The number of calculation steps per hour can be specified by the user, but it is recommended to use a minimum of 1000 calculation steps per hour. The number of report times per hour can as well be set by the user.


Pollutants covered: IndusChemFate is designed to run for organic chemicals. As the exposure period is limited to a maximum of 5 days, the model is not suitable to be run for long-term exposure of substances with accumulation properties.


Population subgroups: The model is meant to simulate worker and consumer exposure in a typical adult with a body weight of 70 kg. Two levels of activity are distinguished, influencing physiological parameters. As physiological parameters are scaled to body weight, changing body weight in the software code, will accordingly change the values of the physiological parameters.

Input: 

Input related to the chemical: For each chemical and its set of subsequent metabolites, a basic set of physico-chemical properties is required (density, molecular weight, vapour pressure, solubility, partition coefficients air:water, octanol:water, octanol:air). Michaelis-Menten parameters Vmax and Km have to be specified for each chemical and its metabolites and for each organ in which metabolism occurs. In case of oral exposure, the absorption rate in the intestine is required.


Input related to the exposure pattern: For airborne exposure, the chemical concentration is required accompanied by starting time and duration of exposure within a 1 day (24 h) period. Activity level, presence of respiratory protection and of dermal protection has to be specified. For dermal exposure, skin deposition of the chemical, start and duration of exposure within a 1 day (24 h) period, skin temperature and affected skin area have to be specified. Defaults are available for skin temperature and affected skin area. For oral exposure, a bolus dose to the stomach and application time.


The user should indicate whether or not exposure is repeated for 5 working days. Start of observation, observation duration, number of simulation steps and number of reported time steps should be filled in.


The model is programmed as a macro in Visual Basic and runs in Excel. Data input is directly into the Excel worksheet.

Output: 

The model generates for each time step, the parent chemical and its metabolites, following information:


  • levels in alveolar air
  • levels in venous blood
  • levels in urine
  • levels in organs and tissues.


The QSPR predicted partition coefficients are part of the output.


Graphs provide a visual presentation of time patterns in alveolar air, venous blood and urine.


The output is generated within the Excel spreadsheet as tables. Results can also be saved in a text file for use in other applications.

Description of processes modelled and of technical details: 

Model description


IndusChemFate has been developed as a model tool in MS-Excel to estimate blood and urine concentration of multiple chemicals, given a certain exposure scenario. Three uptake routes are considered (inhalation, dermal and/or oral) as well as two built-in excercise levels. The model assumes a refererence human of 70 kilograms. The layout of the model (figure 1) is in line with most PBPK models. The model contains 11 body compartments. All human physiological parameters are adopted from reference documents and are scaled to body weight. The impact of exercise on cardiac output and alveolar ventilation that may influence uptake, distribution, metabolism and excretion is also modeled by definition of two levels of exercise (at rest and at light work).


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 Figure 1: Structure of the IndusChemFate model (from Huizer et al., 2010)


IndusChemFate holds some QSPR algorithms to limit the amount of input parameters. The adopted algorithms for partiitoning (blood:air and tissue:blood) are either published in the scientific literature or developed for the IndusChemFate model.


Dermal uptake is estimated by the use of a novel dermal physiologically based module that considers dermal deposition rate and duration of deposition. Evaporation during skin contact is fully accounted for. Oral intake of compounds is considered as a bolus dose that is directly applied to the stomach and then transferred to the intestinal tissue at a first order rate.


Michalis-Menten metabolism kinetics is incorporated in the model, based on the principle of removal of the parent compound at a rate determined by tissue specific Vmax and Km. The subsequent production of one or more metabolites is determined by specific Vmax and Km values for production. The model supports simlation up to 4 subsequent metabolites.


The residence time of the parent compound or one of its metabolites in the human body is furthermore determined by the rate of circulatiion, storage in tissues and the rate of excretion. Enterohepatic circulation is adopted in the model by means of a by-pass from the liver to the intestines at a user-defined rate. Regulation of renal clearance is an option. It can be determined actively by the user of passively by the model using a buit-in cut-off value based on the octanol:water partition coefficient. The other excretion route is via inhalation, based on the blood:air partition coefficient.


Technical details


IndusChemFate has been developed by IndusTox Consult under the Cefic Long Range Initiative (LRI). It is available for free from the LRI Toolbox (http://www.cefic-lri.org/lri-toolbox/induschemfate).


The model is programmed as a macro in Visual Basic and runs in MS Excel. The model is provided as an Excel worksheet. The code is open and can be modified by the user. A user manual, including model algorithms and Visual Basic code is available. A typical run requires less than 1 minute.


The model is easy to use as long as it is run for the substances in the default database. A background in PBPK modeling is required to use the model for other substances to be able to put in the required parameter values and make appropriate choices with regard to physiological processes.

Rationale: 

IndusChemFate is developed as a generic PBPK model for application in first tiers of an assessment and in case of data-poor substances.


There are some limitations to the model in view of wider application:


  • The respiratory system is not described in detail, therefore making the model less suitable for compounds that are present to a significant extent on particles. In case of particle-bound chemicals, particle deposition kinetics in the respiratory system should be described.
  • The model is designed to simulate short-term exposure (to a maximum of 5 days) in worker and consumer populations. Therefore the application domain seems to be limited to chemicals with a short half-life in the body, reaching steady-state within the exposure period.