Human PBPK model for dioxin

Scope

Human PBPK model for dioxin is a tool for calculating dioxin concentrations in human tissues after a given exposure pattern.

Definition

Basic info

Last modification:	04/07/2007	Model version :
Software status :	Free software	OS :	Linux
Supplier :	INERIS	Installation :	See source
Possible developments :	yes	Source :	TOXI/INERIS web site
Supplier address:	INERIS Verneuil en Halatte, France	Referent(s)* :	S. MICALLEF (INERIS) Sandrine.micallef@ineris.fr

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Discipline : keywords: toxicokinetic model, 2,3,7,8-tétra-chloro-p-dioxin (TCDD), PBPK

SCOPE OF THE MODEL

Physiologically Based Toxicokinetic (PBTK) model for Dioxine. The presented PBTK model allows to simulate ingestion exposures to 2,3,7,8-tétra-chloro-p-dioxin (TCDD) for a woman over her whole life. TCDD is a persistent chemical found in trace amounts all over the globe. It accumulates in animal fat all along the trophic chain. Human exposure to TCDD is therefore almost unavoidable, even if in trace amounts. TCDD has multiple effects on health.

MODEL DESCRIPTION

The proposed model is based on a previous one proposed by van der Molen and colleagues in 1996. The model computes various measures of internal dose as a function of time. The superposition of a peak exposure to a time-varying background intake can be described. All ingested TCDD is supposed to be absorbed. TCDD is supposed to distribute between blood, fat, muscles and skin, and viscera. The model equations are solved dynamically (by numerical integration) with the MCSim simulation package to give a good precision both on short-term and long-term scales. The body mass and the volume of the various body tissues change with the age of the simulated individual.

Figure 1 : Toxicokinetic model used to describe TCDD toxicokinetic in the human body. compartments are characterized with volume V and partition coefficient P. Exchanges between are governed by blood flows, F. Elimination is assumed proportional to the elimination constant, ke. The set value of each parameter is given in Table 1. The ingested quantity by unit of time ki (in ng/min), is determined by the exposure scenario.

Table 1 : Numerical values of the parameters of the toxicokinetic model for TCDD in the woman.

Parameter(a)	Symbol	Numerical Value
Ventilation rate	Fp	8,0
Blood over air ventilation rate	R	1,14
Blood flow rates
Fat	Ff	0,09
Liver	Fl	0,24
Muscles and skin	fm	0,18
Viscera	fv	– (b)
Volumes
Total body volume	Vt	– (c)
Fat	Vf	– (c)
Liver	Vl	– (c)
Muscles and skin	Vm	– (c)
Viscera	Vv	– (c)
Partition Coefficient
Fat	Pf	300
Liver	Pl	25
Muscles and skin	Pm	4
Viscera	Pv	10
Elimination constant	ke	8,4510-8 (d)

(a) Units : volumes (L), blood flow (L/min), et elimination constant (min-1). (b) Blood flow rate to viscera is calculated by difference between 1 and the sum of blood flow rates toward the other compartments. (c) Volumes evolve with time. (d) Corresponds to a half-life of 15,6 years.

Figure 1 gives a graphical representation of the model used. Only ingestion exposure is described in this model (the totality of the exposure dose is assumed to be absorbed). The TCDD is supposed to be distributed into different compartments of the body : blood, fat, muscles and skin. The original formulation of van der Molen and coll. regards all these compartments as being with balance in an instantaneous way. This assumption is acceptable only if slow evolutions of absorption are the limiting factor of the kinetics of the product. Since the simulation of a short peak of exposure interests us, we developed a traditional dynamic formulation, specifies at the same time on short scales of time and the long-term.

Model equations Equations defining the proposed model are the following : For quantites of TCDD in fat, viscera, muscle and skin, and liver : (1) (2) (3) (4) La concentration artérielle est calculée par : (5)

The cardiac output, Ft, is proportinal to the ventilation rate, Fp : (1) The body volume evolve as a function of age : (6) The volume of fat, viscera, liver also evolve as a function of age: (7) (8) (9) Volume of "muscles and skin" compartment is calculated as the difference between 90% of the total body volume (because bones are not included) and the other compartments : (10) Units used are : quantities of TCDD are expressed in ng, TCDD concentrations in ng/L, age in years volumes in liter, flows in L/min, the elimination constant in min-1, the ingested quantity by unit of time in ng/min. The body density is assumed equal to 1.

Figure 2 presents the temporal evolution of these parameters for a woman (the evolution is overall similar for a man). The reference averaged values used for the parameters not evolving with time are given in Table 1. The equations of the model were coded using the MCSim software.

Figure 2 : Temporal evolution of volumes for the woman.

VALIDATION

To be done

APPLICATIONS EXAMPLES

Example of the use of this model can be found in the paper by Bois

See also

• Van der Molen GW, Kooijman BALM, Wittsiepe J, et al. Estimation of dioxin and furan elimination rates with a pharmacokinetic model

JOURNAL OF EXPOSURE ANALYSIS AND ENVIRONMENTAL EPIDEMIOLOGY 10 (6): 579-585 Part 1 NOV-DEC 2000.

• Van der Molen GW, Kooijman SALM, Michalek JE, et al. The estimation of elimination rates of persistent compounds: A re-analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in Vietnam veterans CHEMOSPHERE 37 (9-12): 1833-1844 OCT-NOV 1998.

Model template

Dioxin PBPK model
The results are total amounts (ng) of dioxin, except blood concentration (ng/l). See the model documentation
The input data used for this variable: Intake at age 0 - 5 a (ng/min) {{{dose1}}} Intake at age 5 - 10 a (ng/min) {{{dose2}}} Intake at age 10-15 a (ng/min) {{{dose3}}} Intake at age 15 - 40 a (ng/min) {{{dose4}}} Intake at age 40 - a (ng/min) {{{dose5}}} Start of peak intake (days) {{{peakstart}}} End of peak intake (days) {{{peakend}}} Additional peak intake (ng/min) {{{peakdose}}}
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