Human PBPK model for dioxin: Difference between revisions

From Opasnet
Jump to navigation Jump to search
mNo edit summary
mNo edit summary
Line 1: Line 1:
==Scope==
== Scope ==
'''Human PBPK model for dioxin''' is a tool for calculating dioxin concentrations in human tissues after a given exposure pattern.


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


===Basic info===
== Definition  ==
 
=== Basic info ===


{| {{prettytable}}
{| {{prettytable}}
|Last modification:
|-
|04/07/2007
| Last modification:  
|Model version :
| 04/07/2007  
|
| Model version :  
|----
|  
|Software status :
|-
|Free software
| Software status :  
|OS :
| Free software  
|Linux
| OS :  
|----
| Linux
|Supplier :
|-
|INERIS
| Supplier :  
|Installation :
| INERIS  
|See source
| Installation :  
|----
| See source
|Possible developments :
|-
|yes
| Possible developments :  
|Source :
| yes  
|TOXI/INERIS web site <ref>http://toxi.ineris.fr/activites/toxicologie_quantitative/toxicocinetique/modeles/dioxine/sub_dioxine.php</ref>
| Source&nbsp;:  
|----
| TOXI/INERIS web site <ref>http://toxi.ineris.fr/activites/toxicologie_quantitative/toxicocinetique/modeles/dioxine/sub_dioxine.php</ref>
|Supplier address:
|-
|INERIS Verneuil en Halatte, France  
| Supplier address:  
|Referent(s)* :
| INERIS Verneuil en Halatte, France  
|S. MICALLEF (INERIS)
| Referent(s)*&nbsp;:  
Sandrine.micallef@ineris.fr
| S. MICALLEF (INERIS)  
|----
Sandrine.micallef@ineris.fr  
 
|}
|}


Discipline : keywords: toxicokinetic model, 2,3,7,8-tétra-chloro-p-dioxin (TCDD), PBPK
Discipline&nbsp;: keywords: toxicokinetic model, 2,3,7,8-tétra-chloro-p-dioxin (TCDD), PBPK  
 
=== Scope of the mode ===
 
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.


===SCOPE OF THE MODEL===
=== Model description&nbsp;<br>  ===


Physiologically Based Toxicokinetic (PBTK) model for Dioxine.
The proposed model is based on a previous one proposed by van der Molen and colleagues in 1996<ref name="molen">Van der Molen, G. W., S. A. L. M. Kooijman and W. Slob (1996). "A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD." Fundamental and  Applied Toxicology 31: 83-94.</ref>. 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.  
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 ===
Figure 1&nbsp;: Toxicokinetic model used to describe TCDD toxicokinetic in the human body<ref name="molen" />. 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.
The proposed model is based on a previous one proposed by van der Molen and colleagues in 1996<ref name="molen">Van der Molen, G. W., S. A. L. M. Kooijman and W. Slob (1996). "A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD." Fundamental and  Applied Toxicology 31: 83-94.</ref>. 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.
 
 
Table 1&nbsp;: Numerical values of the parameters of the toxicokinetic model for TCDD in the woman.  
Figure 1 : Toxicokinetic model used to describe TCDD toxicokinetic in the human body<ref name="molen"/>. 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.
{| {{prettytable}}
{| {{prettytable}}
|Parameter(a)
|-
|Symbol
| Parameter(a)  
|Numerical Value
| Symbol  
|----
| Numerical Value
|Ventilation rate
|-
|Fp
| Ventilation rate  
|8,0
| Fp  
|----
| 8,0
|Blood over air ventilation rate  
|-
|R
| Blood over air ventilation rate  
|1,14
| R  
|----
| 1,14
|Blood flow rates  
|-
|
| Blood flow rates  
|
|  
|----
|  
|Fat
|-
|Ff
| Fat  
|0,09
| Ff  
|----
| 0,09
|Liver
|-
|Fl
| Liver  
|0,24
| Fl  
|----
| 0,24
|Muscles and skin
|-
|fm
| Muscles and skin  
|0,18
| fm  
|----
| 0,18
|Viscera
|-
|fv
| Viscera  
|– (b)
| fv  
|----
| – (b)
|Volumes
|-
|
| Volumes  
|
|  
|----
|  
|Total body volume
|-
|Vt
| Total body volume  
|– (c)
| Vt  
|----
| – (c)
|Fat
|-
|Vf
| Fat  
|– (c)
| Vf  
|----
| – (c)
|Liver
|-
|Vl
| Liver  
|– (c)
| Vl  
|----
| – (c)
|Muscles and skin
|-
|Vm
| Muscles and skin  
|– (c)
| Vm  
|----
| – (c)
|Viscera
|-
|Vv
| Viscera  
|– (c)
| Vv  
|----
| – (c)
|Partition Coefficient
|-
|
| Partition Coefficient  
|
|  
|----
|  
|Fat
|-
|Pf
| Fat  
|300
| Pf  
|----
| 300
|Liver
|-
|Pl
| Liver  
|25
| Pl  
|----
| 25
|Muscles and skin
|-
|Pm
| Muscles and skin  
|4
| Pm  
|----
| 4
|Viscera
|-
|Pv
| Viscera  
|10
| Pv  
|----
| 10
|Elimination constant
|-
|ke
| Elimination constant  
|8,4510-8 (d)
| ke  
|----
| 8,4510-8 (d)
|}
|}


(a) Units : volumes (L), blood flow (L/min), et elimination constant (min-1).
(a) Units&nbsp;: 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.  
(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.<ref name="molen"/> 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<ref>Gerlowski, L. E. and R. K. Jain (1983). "Physiologically based pharmacokinetic modeling: principles and applications." Journal of Pharmaceutical Sciences 72: 1103-1127.</ref>, specifies at the same time on short scales of time and the long-term.  
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&nbsp;: blood, fat, muscles and skin. The original formulation of van der Molen and coll.<ref name="molen" /> 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<ref>Gerlowski, L. E. and R. K. Jain (1983). "Physiologically based pharmacokinetic modeling: principles and applications." Journal of Pharmaceutical Sciences 72: 1103-1127.</ref>, specifies at the same time on short scales of time and the long-term.  


Model equations  
Model equations Equations defining the proposed model are the following&nbsp;: For quantites of TCDD in fat, viscera, muscle and skin, and liver&nbsp;: (1) (2) (3) (4) La concentration artérielle est calculée par&nbsp;: (5)  
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 :
The cardiac output, Ft, is proportinal to the ventilation rate, Fp&nbsp;: (1) The body volume evolve as a function of age&nbsp;: (6) The volume of fat, viscera, liver also evolve as a function of age<ref name="molen" />: (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&nbsp;: (10) Units used are&nbsp;: 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.  
(1)
The body volume evolve as a function of age :
(6)
The volume of fat, viscera, liver also evolve as a function of age<ref name="molen"/>:
(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<ref>Bois, F. Y. and D. Maszle (1997). "MCSim: a simulation program." Journal of Statistical Software 2(9): [http://toxi.ineris.fr/activites/toxicologie_quantitative/mcsim/mcsim.php].</ref>.  
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<ref>Bois, F. Y. and D. Maszle (1997). "MCSim: a simulation program." Journal of Statistical Software 2(9): [http://toxi.ineris.fr/activites/toxicologie_quantitative/mcsim/mcsim.php].</ref>.  


<br> Figure 2&nbsp;: Temporal evolution of volumes for the woman<ref name="molen" />.  
Figure 2 : Temporal evolution of volumes for the woman<ref name="molen"/>.


===VALIDATION===
=== Validation ===
To be done


===APPLICATIONS EXAMPLES===
To be done
Example of the use of this model can be found in the paper by
Bois<ref>Bois, F. Y. (2003). "Modélisation toxicocinétique de la concentration sanguine de 2,3,7,8-tetrachloro-p-dioxine après ingestion chez la femme." Environnement, Risques et Santé 2(1). [Toxicokinetic modelling of 2,3,7,8-tétrachloro-p-dioxin blood concentration after ingestion by women. Environnement, Risque et Santé, (2003) 2:45-53. ]</ref>


==See also==
=== Applications examples ===
 
Example of the use of this model can be found in the paper by Bois<ref>Bois, F. Y. (2003). "Modélisation toxicocinétique de la concentration sanguine de 2,3,7,8-tetrachloro-p-dioxine après ingestion chez la femme." Environnement, Risques et Santé 2(1). [Toxicokinetic modelling of 2,3,7,8-tétrachloro-p-dioxin blood concentration after ingestion by women. Environnement, Risque et Santé, (2003) 2:45-53. ]</ref>
 
== 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 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.
*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 inputs===
=== Model inputs ===


All intakes are given in ng/min. A typical unit is pg/d; to change from the latter to the former, divide by 1440000.
All intakes are given in ng/min. A typical unit is pg/d; to change from the latter to the former, divide by 1440000.  


Background exposure parameters:
Background exposure parameters:  
*dose1: intake of dioxin during age 0 - 5 years
 
*dose2: intake of dioxin during age 5 - 10 years
*dose1: intake of dioxin during age 0 - 5 years  
*dose3: intake of dioxin during age 10 -15 years
*dose2: intake of dioxin during age 5 - 10 years  
*dose4: intake of dioxin during age 15 - 40 years
*dose3: intake of dioxin during age 10 -15 years  
*dose4: intake of dioxin during age 15 - 40 years  
*dose5: intake of dioxin during age 40 - years
*dose5: intake of dioxin during age 40 - years


Peak exposure parameters (in addition to the background)
Peak exposure parameters (in addition to the background)  
*peakstart: start of the peak exposure period (in days of age)
 
*peakend: end of the peak exposure period (in days of age)
*peakstart: start of the peak exposure period (in days of age)  
*peakend: end of the peak exposure period (in days of age)  
*peakdose: Additional intake of dioxin during the peak period (in ng/min)
*peakdose: Additional intake of dioxin during the peak period (in ng/min)


==Model template==
== Model template ==


{{Dioxin PBPK model
{{Dioxin PBPK model
Line 205: Line 191:
|dose4=0.000173611
|dose4=0.000173611
|dose5=0.000173611
|dose5=0.000173611
}}
}}  


==REFERENCES==
== References<br> ==


<references/>
<references />

Revision as of 07:43, 12 March 2009

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 [1]
Supplier address: INERIS Verneuil en Halatte, France Referent(s)* : S. MICALLEF (INERIS)

Sandrine.micallef@ineris.fr

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

Scope of the mode

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[2]. 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[2]. 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.[2] 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[3], 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[2]: (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[4].


Figure 2 : Temporal evolution of volumes for the woman[2].

Validation

To be done

Applications examples

Example of the use of this model can be found in the paper by Bois[5]

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 inputs

All intakes are given in ng/min. A typical unit is pg/d; to change from the latter to the former, divide by 1440000.

Background exposure parameters:

  • dose1: intake of dioxin during age 0 - 5 years
  • dose2: intake of dioxin during age 5 - 10 years
  • dose3: intake of dioxin during age 10 -15 years
  • dose4: intake of dioxin during age 15 - 40 years
  • dose5: intake of dioxin during age 40 - years

Peak exposure parameters (in addition to the background)

  • peakstart: start of the peak exposure period (in days of age)
  • peakend: end of the peak exposure period (in days of age)
  • peakdose: Additional intake of dioxin during the peak period (in ng/min)

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) 0.000173611
  • Intake at age 5 - 10 a (ng/min) 0.000173611
  • Intake at age 10-15 a (ng/min) 0.000173611
  • Intake at age 15 - 40 a (ng/min) 0.000173611
  • Intake at age 40 - a (ng/min) 0.000173611
  • Start of peak intake (days) 100
  • End of peak intake (days) 1000
  • Additional peak intake (ng/min) 0.000001

Click here to run the model

References

  1. ↑ http://toxi.ineris.fr/activites/toxicologie_quantitative/toxicocinetique/modeles/dioxine/sub_dioxine.php
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Van der Molen, G. W., S. A. L. M. Kooijman and W. Slob (1996). "A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD." Fundamental and Applied Toxicology 31: 83-94.
  3. ↑ Gerlowski, L. E. and R. K. Jain (1983). "Physiologically based pharmacokinetic modeling: principles and applications." Journal of Pharmaceutical Sciences 72: 1103-1127.
  4. ↑ Bois, F. Y. and D. Maszle (1997). "MCSim: a simulation program." Journal of Statistical Software 2(9): [1].
  5. ↑ Bois, F. Y. (2003). "Modélisation toxicocinétique de la concentration sanguine de 2,3,7,8-tetrachloro-p-dioxine après ingestion chez la femme." Environnement, Risques et Santé 2(1). [Toxicokinetic modelling of 2,3,7,8-tétrachloro-p-dioxin blood concentration after ingestion by women. Environnement, Risque et Santé, (2003) 2:45-53. ]
Retrieved from "https://en.opasnet.org/index.php?title=Human_PBPK_model_for_dioxin&oldid=8327"