This function initializes the parameters needed in the functions solve_dermal_pbtk.
parameterize_dermal_pbtk(
chem.cas = NULL,
chem.name = NULL,
dtxsid = NULL,
model.type = "dermal_1subcomp",
method.permeability = "UK-Surrey",
species = "Human",
default.to.human = FALSE,
tissuelist = list(liver = c("liver"), kidney = c("kidney"), lung = c("lung"), gut =
c("gut"), skin = c("skin")),
force.human.clint.fup = FALSE,
clint.pvalue.threshold = 0.05,
adjusted.Funbound.plasma = TRUE,
adjusted.Clint = TRUE,
regression = TRUE,
suppress.messages = FALSE,
restrictive.clearance = TRUE,
minimum.Funbound.plasma = 1e-04,
skin_depth = 0.12,
skin.pH = 7,
BW = NULL,
height = 175,
totalSA = NULL,
Kvehicle2water = "water",
InfiniteDose = 0,
million.cells.per.gliver = 110,
liver.density = 1.05,
kgutabs = 2.18,
Caco2.options = NULL
)Body Weight, kg.
Hepatic Clearance, L/h/kg BW.
Fraction of the oral dose absorbed, i.e. the fraction of the dose that enters the gutlumen.
The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al.(2008)
Fraction of skin depth in strateum corneum so that the depth of the SC is Fskin_depth_sc*skin_depth. This parameter does not appear when model.type="dermal_1subcomp".
Fraction of skin depth in combined viable epidermis and dermis so that the depth of the ED is Fskin_depth_ed*skin_depth. This parameter does not appear when model.type="dermal_1subcomp".
Fraction of skin exposed.
Fraction of plasma that is not bound.
Percent volume of red blood cells in the blood.
If InfiniteDose=1, infinite dosing is assumed and Cvehicle_infinite is used in place of Cvehicle; if InfiniteDose=0, finite dosing is assumed and Avehicle is used for dosing. When InfiniteDose=1, the state variable Avehicle does not have meaning.
Ratio of concentration of chemical in blood to air, calculated using calc_kair.
Ratio of concentration of chemical in gut tissue to unbound concentration in plasma.
Rate that chemical enters the gut from gutlumen, 1/h.
Ratio of concentration of chemical in kidney tissue to unbound concentration in plasma.
Ratio of concentration of chemical in liver tissue to unbound concentration in plasma.
Ratio of concentration of chemical in lung tissue to unbound concentration in plasma.
Ratio of concentration of chemical in red blood cells to unbound concentration in plasma.
Ratio of concentration of chemical in rest of body tissue to unbound concentration in plasma.
Ratio of concentration of chemical in skin tissue to unbound concentration in plasma.
Partition coefficient between exposed skin and vehicle. This parameter only appears when model.type="dermal_1subcomp" and is replaced by Ksc2vehicle when model.type="dermal".
Partition coefficient between SC and vehicle. This parameter does not appear when model.type="dermal_1subcomp".
Partition coefficient between ED and SC. This parameter does not appear when model.type="dermal_1subcomp".
?
Millions cells per gram of liver tissue.
Molecular Weight, g/mol.
Permeability of the skin, cm/h. When model.type="dermal_1subcomp", this parameter changes depending on method.permeability. When model.type="dermal", this parameter is replaced by Pvehicle2sc and Psc2ed.
Permeability of the stratum corneum (SC), cm/h. This parameter does not appear when model.type="dermal_1subcomp".
Permeability of the combined viable epidermis and dermis layer of the skin ("ed"), cm/h. This parameter does not appear when model.type="dermal_1subcomp".
Unscaled alveolar ventilation rate, L/h/kg BW^3/4.
Cardiac Output, L/h/kg BW^3/4.
Glomerular Filtration Rate, L/h/kg BW^3/4, volume of fluid filtered from kidney and excreted.
Fraction of cardiac output flowing to the gut.
Fraction of cardiac output flowing to the kidneys.
Fraction of cardiac output flowing to the liver.
Fraction of cardiac output flowing to the lung.
Fraction of cardiac output flowing to the skin, or to the ed layer of the skin when model.type="dermal".
The ratio of the concentration of the chemical in the blood to the concentration in the plasma from available_rblood2plasma.
Skin depth, cm.
Total body surface area, cm^2.
Volume of the arteries per kg body weight, L/kg BW.
Volume of the gut per kg body weight, L/kg BW.
Volume of the kidneys per kg body weight, L/kg BW.
Volume of the liver per kg body weight, L/kg BW.
Volume of the lungs per kg body weight, L/kg BW.
Volume of the rest of the body per kg body weight, L/kg BW.
Volume of the veins per kg body weight, L/kg BW.
Volume of the skin per kg body weight, L/kg BW.
Volume of the sc or upper layer of the skin per kg body weight, L/kg BW. This parameter does not appear when model.type="dermal_1subcomp".
Volume of the combined viable epidermis and dermis layer of the skin per kg body weight, L/kg BW. This parameter does not appear when model.type="dermal_1subcomp".
Either the chemical name or the CAS number must be specified.
Either the chemical name or the CAS number must be
specified.
Parameters include
tissue:plasma partition coefficients, organ volumes, and flows
for the tissue lumping scheme specified by argument tissuelist.
Tissure:(fraction unbound in) plasma partitition coefficients are predicted
via Schmitt (2008)'s method as modified by Pearce et al. (2017) using
predict_partitioning_schmitt. Organ volumes and flows are
retrieved from table physiology.data.
Tissues must be described in table tissue.data.
By default, this function initializes the parameters needed in the functions
solve_pbtk, calc_css, and others using the httk
default generic PBTK model (for oral and intravenous dosing only).
The default PBTK model includes an explicit first pass of the chemical through
the liver before it becomes available to systemic blood. We model systemic oral bioavailability as
Fbio=Fabs*Fgut*Fhep.
Only if Fbio
has been measured in vivo and is found in
table chem.physical_and_invitro.data then we set
Fabs*Fgut
to the measured value divided by
Fhep
where Fhep
is estimated from in vitro TK data using
calc_hep_bioavailability.
If Caco2 membrane permeability data or predictions
are available Fabs is estimated
using calc_fabs.oral.
Intrinsic hepatic metabolism is used to very roughly estimate
Fgut
using calc_fgut.oral.
EPA's DSSTox Structure ID (https://comptox.epa.gov/dashboard) the chemical must be identified by either CAS, name, or DTXSIDs.
Choice of dermal model, either the default "dermal_1subcomp" for the model with 1 compartment for the skin; or (not usable yet) "dermal" for the model with 2 sub compartments (a sc and ed layer) for skin which defaults to the sc layer being the stratum corneum and the ed layer being the combined viable epidermis and dermis.
For "dermal_1subcomp" model, method of calculating the permeability coefficient, P, either "Potts-Guy" or "UK-Surrey". Default is "UK-Surrey" (Sawyer et al., 2016 and Chen et al., 2015), which uses Fick's law of diffusion to calculate P. For "dermal" model, this parameter is ignored.
Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").
Substitutes missing animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma).
Specifies compartment names and tissues groupings.
Remaining tissues in tissue.data are lumped in the rest of the body.
However, solve_dermal_pbtk only works with the default parameters.
Forces use of human values for hepatic intrinsic clearance and fraction of unbound plasma if true.
Hepatic clearance for chemicals where the in vitro clearance assay result has a p-values greater than the threshold are set to zero.
Uses Pearce et al. (2017) lipid binding adjustment for Funbound.plasma (which impacts partition coefficients) when set to TRUE (Default).
Uses Kilford et al. (2008) hepatocyte incubation binding adjustment for Clint when set to TRUE (Default).
Whether or not to use the regressions in calculating partition coefficients.
Whether or not the output message is suppressed.
In calculating hepatic.bioavailability, protein binding is not taken into account (set to 1) in liver clearance if FALSE.
Monte Carlo draws less than this value are set equal to this value (default is 0.0001 -- half the lowest measured Fup in our dataset).
skin_depth of skin, cm, used in calculating P.
pH of dermis/skin, used in calculating P and Kskin2vehicle.
Body weight (kg)
Height in cm, used in calculating totalSA.
Total body surface area (cm^2)
Partition coefficient for the vehicle (sometimes called the vehicle) carrying the chemical to water. Default is "water", which assumes the vehicle is water. Other optional inputs are "octanol", "olive oil", or a numeric value.
If TRUE, we assume infinite dosing (i.e., a constant unchanging concentration of chemical in the vehicle is considered) and Cvehicle is a constant. If FALSE (default), dosing is finite and Cvehicle changes over time.
Hepatocellularity (defaults to 110 10^6 cells/g-liver, from Carlile et al. (1997))
Liver density (defaults to 1.05 g/mL from International Commission on Radiological Protection (1975))
Oral absorption rate from gut (defaults to 2.18 1/h from Wambaugh et al. (2018))
A list of options to use when working with Caco2 apical to
basolateral data Caco2.Pab, default is Caco2.options = list(Caco2.default = 2,
Caco2.Fabs = TRUE, Caco2.Fgut = TRUE, overwrite.invivo = FALSE, keepit100 = FALSE). Caco2.default sets the default value for
Caco2.Pab if Caco2.Pab is unavailable. Caco2.Fabs = TRUE uses Caco2.Pab to calculate
fabs.oral, otherwise fabs.oral = Fabs. Caco2.Fgut = TRUE uses Caco2.Pab to calculate
fgut.oral, otherwise fgut.oral = Fgut. overwrite.invivo = TRUE overwrites Fabs and Fgut in vivo values from literature with
Caco2 derived values if available. keepit100 = TRUE overwrites Fabs and Fgut with 1 (i.e. 100 percent) regardless of other settings.
Annabel Meade, John Wambaugh, and Robert Pearce
Chen, L., Han, L., Saib, O. and Lian, G. (2015). In Silico Prediction of Percutaneous Absorption and Disposition Kinetics of Chemicals. Pharmaceutical Research 32, 1779-93, 10.1007/s11095-014-1575-0
kilford2008hepatocellularhttk
Potts, R. O., Guy, R. H. (1992). Predicting skin permeability. Pharmaceutical research 9(5), 663-9, 10.1002/ajim.4700230505.
Sawyer, M. E., Evans, M. V., Wilson, C. A., Beesley, L. J., Leon, L. S., Eklund, C. R., Croom, E. L., Pegram, R. A. (2016). Development of a human physiologically based pharmacokinetic (PBPK) model for dermal permeability for lindane. Toxicology Letters 245, 106-9, 10.1016/j.toxlet.2016.01.008
solve_dermal_pbtk
predict_partitioning_schmitt
apply_clint_adjustment
tissue.data
physiology.data
params <- parameterize_dermal_pbtk(chem.cas="80-05-7")
params <- parameterize_dermal_pbtk(chem.cas="80-05-7", model.type="dermal_1subcomp",
method.permeability="Potts-Guy")
params <- parameterize_dermal_pbtk(chem.cas="80-05-7", model.type="dermal",
Kvehicle2water = "octanol")
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