Available kinetic models

Physiologically based toxicokinetic (PBTK) models, or kinetic models for short, are mathematical representations of the animal or human body aimed at describing and predicting the time course distribution of chemicals in tissues and organs. Those internal dose metrics can usefully replace external exposure dose in the derivation of the quantitative dose-response relationships and following risk assessments. PBTK models can simulate both internal doses from exposure scenarios (forward dosimetry) and external dose from biomonitoring data (reverse dosimetry).

The following generic PBTK models are currently implemented in MCRA:

EuroMix Generic PBTK model v6

Cosmos version 6 (received 3/27/2019)

Model aliases: Cosmos6, CosmosV6.

Table 189 Exposure routes (forcings)
Id Description Unit Order

Dietary

Dietary exposure

mmoles

0

Dermal

Dermal exposure

mmoles

1

Inhalation

Inhalatory exposure

mmoles

2

Table 190 Output
Id Description ScalingFactor MultiplicationFactor Unit Order

CTotal

Total concentration

mM

0

CVen

Venous blood concentration

scVBlood

0.66667

mM

1

CArt

Arterial blood concentration

scVBlood

0.33333

mM

2

CFat

Fat (adipose) tissue concentration

scVFat

mM

3

CPoor

Poorly perfused tissue (muscle) concentration

mM

4

CRich

Richly perfused tissue (viscera) concentration

scVRich

mM

5

CLiver

Liver concentration

scVLiver

mM

6

CSkin_u

Viable unexposed skin concentration

mM

7

CSkin_e

Viable exposed skin concentration

BSA, Height_vs, fsA_exposed

mM

8

CSkin_sc_u

Skin unexposed stratum corneum concentration

mM

9

CSkin_sc_e

Skin exposed stratum corneum concentration

BSA, Height_vs, fsA_exposed

mM

10

Table 191 Input
Id Description Unit Type Order

BM

Body mass

kg

Physiological

0

BSA

Body surface area (internally scaled by an allometric scaling factor s = 70/BM^0.3)

dm2

Physiological

1

scVFat

Fat as fraction of total body volume

Physiological

2

scVRich

Richly perfused tissues (viscera) as fraction of total body volume

Physiological

3

scVLiver

Liver as fraction of total body volume

Physiological

4

scVBlood

Blood as fraction of total body volume

Physiological

5

Height_sc

Skin thickness

decimeter

Physiological

6

Height_vs

Viable skin

Physiological

7

scFBlood

Total blood flow per unit mass

L/h/kg

Physiological

8

scFFat

Fat fraction of total blood flow going to compartments

Physiological

9

scFPoor

Poorly perfused tissues (muscles) fraction of total blood flow going to compartments

Physiological

10

scFLiver

Liver fraction of total blood flow going to compartments

Physiological

11

scFSkin

Skin fraction of total blood flow going to compartments

Physiological

12

Falv

Alveolar ventilation rate

L/h

Physiological

13

mic

Microsomal proteins content

mg/gr liver

Physiological

14

Kp_sc_vs

Diffusion rate from stratum corneum to viable skin

decimeter/h

Metabolic

22

Ke

Renal excretion rate

L/h

Metabolic

23

Michaelis

Flag for Michaelis-Menten vs linear metabolism (0 = linear)

Metabolic

24

Vmax

Maximum rate of metabolism

mmoles/h/L liver

Metabolic

25

Km

Michaelis-Menten constant for metabolism

mM

Metabolic

26

CLH

Hepatic metabolic clearance

Metabolic

27

fub

Unbound fraction in blood

Metabolic

28

Frac

Fraction absorbed by the gut

Metabolic

29

kGut

Oral 1st order absorption rate constant

1/h

Metabolic

30

fSA_exposed

Fraction of skin surface area actually exposed

Metabolic

35

EuroMix Generic PBTK model v5

Cosmos version 5 (adapted 9/11/2018)

Model aliases: Cosmos4, CosmosV4, Cosmos5, CosmosV5.

Table 192 Exposure routes (forcings)
Id Description Unit Order

Dietary

Dietary exposure

mmoles

0

Dermal

Dermal exposure

mmoles

1

Inhalation

Inhalatory exposure

mmoles

2

Table 193 Output
Id Description ScalingFactor MultiplicationFactor Unit Order

CVen

Venous blood

scVBlood

0.66667

mM

0

CArt

Arterial blood

scVBlood

0.33333

mM

1

CFat

Fat tissues

scVFat

mM

2

CPoor

Muscle tissues

mM

3

CRich

Viscera

scVRich

mM

4

CLiver

Liver

scVLiver

mM

5

CSkin_u

Viable skin, unexposed

mM

6

CSkin_e

Viable skin, exposed

BSA, Height_vs, fsA_exposed

mM

7

CSkin_sc_u

Skin stratum corneum, unexposed

mM

8

CSkin_sc_e

Skin stratum corneum, exposed

BSA, Height_vs, fsA_exposed

mM

9

Table 194 Input
Id Description Unit Type Order

BM

Body mass

kg

Physiological

0

BSA

Body skin surface area

dm2

Physiological

1

scVFat

Fat as fraction of total body volume

Physiological

2

scVRich

Richly perfused tissues (viscera) as fraction of total body volume

Physiological

3

scVLiver

Liver as fraction of total body volume

Physiological

4

scVBlood

Blood as fraction of total body volume

Physiological

5

Height_sc

Skin thickness

decimeter

Physiological

6

Height_vs

Viable skin

Physiological

7

scFBlood

Total blood flow per unit mass

L/h/kg

Physiological

8

scFFat

Fat fraction of total blood flow going to compartments

Physiological

9

scFPoor

Poorly perfused tissues (muscles) fraction of total blood flow going to compartments

Physiological

10

scFLiver

Liver fraction of total blood flow going to compartments

Physiological

11

scFSkin

Skin fraction of total blood flow going to compartments

Physiological

12

Falv

Alveolar ventilation rate

L/h

Physiological

13

mic

Microsomal proteins content

mg/gr liver

Physiological

14

PCAir

Partition coefficient: blood over air

Partition coefficient

15

Kp_sc_vs

Diffusion rate from stratum corneum to viable skin

decimeter/h

Metabolic

22

Ke

Renal excretion rate

L/h

Metabolic

23

Michaelis

Flag for Michaelis-Menten vs linear metabolism (0 = linear)

Metabolic

24

Vmax

Maximum rate of metabolism

mmoles/h/L liver

Metabolic

25

Km

Michaelis-Menten constant

mM

Metabolic

26

CLH

Hepatic clearance

Metabolic

27

fup

Unbound fraction in blood

Metabolic

28

Frac

Fraction absorbed by the gut

Metabolic

29

kGut

Oral 1st order absorption rate constant

1/h

Metabolic

30

fSA_exposed

Fraction of skin surface area actually exposed

Metabolic

35

Generic Model BPA

Generic model Cecile Karrer 23 juli 2018

Model aliases: PBPKModel_BPA, PBPKModelBPA, ModelBPA, BPA.

Table 195 Exposure routes (forcings)
Id Description Unit Order

Dietary

Dietary exposure

nmoles

0

Oral

Oral exposure

nmoles

1

Dermal

Dermal exposure

nmoles

2

Inhalation

Inhalation exposure

nmoles

3

Table 196 Output
Id Description ScalingFactor MultiplicationFactor Unit Order

CPlasmaOut

Concentration in plasma

nmol/L

0

CGonadOut

Concentration in gonads

nmol/L

1

AurinebpaOut

Cumulative excretion of BPA in urine

nmol/L

2

AurinegOut

Cumulative excretion of BPA-g in urine

nmol/L

3

AurineTotalOut

Cumulative excretion of BPA and metabolites in urine

nmol/L

4

Table 197 Input
Id Description Unit Type Order

BW

Bodyweight

kg

Physiological

0

QCC

Cardiac output

L/min

Physiological

1

QgonadC

Fractional blood flow to gonads

Physiological

2

QliverC

Fractional blood flow to liver

Physiological

3

QfatC

Fractional blood flow to fat tissue

Physiological

4

QbrainC

Fractional blood flow to brain

Physiological

5

QskinC

Fractional blood flow to skin

Physiological

6

QmuscleC

Fractional blood flow to gonads

Physiological

7

VplasmaC

Fractional volume of plasma

Physiological

8

VfatC

Fractional volume of fat tissue

Physiological

9

VliverC

Fractional volume of liver tissue

Physiological

10

VbrainC

Fractional volume of brain tissue

Physiological

11

VskinC

Fractional volume of skin tissue

Physiological

12

VgonadC

Fractional volume of gonads

Physiological

13

VmuscleC

Fractional volume of muscle tissue

Physiological

14

VrichC

Fractional volume of richly perfused tissue

Physiological

15

VbodygC

Distribution volume of BPA-g

Physiological

16

MW

Molecular weight

g/mol

Chemical property

18

pliver

Partition coefficient liver to blood

Partition coefficient

19

pfat

Partition coefficient fat to blood

Partition coefficient

20

pslow

Partition coefficient slowly perfused tissue to blood

Partition coefficient

21

prich

Partition coefficient richly perfused tissue to blood

Partition coefficient

22

pgonad

Partition coefficient gonads to blood

Partition coefficient

23

pbrain

Partition coefficient brain to blood

Partition coefficient

24

pskin

Partition coefficient skin to blood

Partition coefficient

25

geC

Gastric emptying

1/h/kg bw^-0.25

Metabolic

26

k0C

Oral uptake from the stomach into the liver

1/h/kg bw^-0.25

Metabolic

27

k1C

Oral uptake from the small intestine into the liver

1/h/kg bw^-0.25

Metabolic

28

k4C

Fecal elimination from small intestine after oral administration

1/h/kg bw^-0.25

Metabolic

29

kGIingC

Transport of glucuronide from enterocytes into serum

1/h/kg bw^-0.25

Metabolic

30

kGIinsC

Transport of sulfate from enterocytes into serum

1/h/kg bw^-0.25

Metabolic

31

kmgutg

Km of Glucuronidation in the gut

nM

Metabolic

32

vmaxgutgC

Vmax of Glucuronidation in the gut

nmol/h/kg bw

Metabolic

33

fgutg

Correction factor of glucuronidation in the gut

Metabolic

34

kmguts

Km of Sulfation in the gut

nM

Metabolic

35

vmaxgutsC

Vmax of Sulfation in the gut

nmol/h/kg bw

Metabolic

36

fguts

Correction factor of sulfation in the gut

Metabolic

37

met1g

Fraction of glucuronide in the liver taken up directly into serum (the rest undergoes EHR)

Metabolic

38

met1s

Fraction of sulfate in the liver taken up directly into serum

Metabolic

39

enterocytes

Sum of enterocytes weights in duodenum, jejunum and ileum

L

Metabolic

40

kmliver

Km of Glucuronidation in the liver

nM

Metabolic

41

vmaxliverC

Vmax of Glucuronidation in the liver

nmol/h/g liver

Metabolic

42

fliverg

Correction factor of glucuronidation in the liver

Metabolic

43

kmlivers

Km of Sulfation in the liver

nM

Metabolic

44

vmaxliversC

Vmax of Sulfation in the liver

nmol/h/g liver

Metabolic

45

flivers

Correction factor of sulfation in the liver

Metabolic

46

EHRtime

Time until EHR occurs

h

Metabolic

47

EHRrateC

EHR of glucuronide

1/h/kg bw^-0.25

Metabolic

48

k4C_IV

Fecal elimination of glucuronide from the EHR compartment

1/h/kg bw^-0.25

Metabolic

49

kurinebpaC

Clearance, urine excretion of parent compound

L/h/kg bw^0.75

Metabolic

50

kurinebpagC

Clearance, urine excretion of glucuronide

L/h/kg bw^0.75

Metabolic

51

kurinebpasC

Clearance, urine excretion of sulfate

L/h/kg bw^0.75

Metabolic

52

vreabsorptiongC

Vmax for renal reabsorption of glucuronide

nmol/h/kg bw^0.75

Metabolic

53

vreabsorptionsC

Vmax for renal reabsorption of sulfate

nmol/h/kg bw^0.75

Metabolic

54

kreabsorptiong

Km for renal reabsorption of glucuronide

nM

Metabolic

55

kreabsorptions

Km for renal reabsorption of sulfate

nM

Metabolic

56

kenterobpagC

EHR of parent compound due to biliary excretion of glucuronide

1/h/kg bw^-0.25

Metabolic

57

kenterobpasC

EHR of parent compound due to biliary excretion of sulfate

1/h/kg bw^-0.25

Metabolic

58

EoA_O

Extent of oral absorption

Physiological

61

period_O

uptake period

h

External

63

t0_O

time point at which dosing starts

h

External

65

EoA_D

Extent of dermal absorption from TP

Physiological

68

aHL_D

Half-life for dermal penetration

h

External

70

period_D

Uptake period dermal exposure from TP

h

External

72

t0_D

Time points at which dermal dosing from TP starts

h

External

74

EoA_D2

Extent of dermal absorption from PCPs

Physiological

77

aHL_D2

Half-life for dermal penetration from PCPs

h

External

79

period_D2

Uptake period dermal exposure from PCPs

h

External

81

t0_D2

Time points at which dermal dosing from PCPs starts

h

External

83

BW075

BW^0.75

kg^0.75

External

103

BW025

BW^0.25

kg^0.25

External

104

Note

Additional kinetic models can be implemented, please contact the MCRA administrator.