parameterize_gas_pbtk {httk}

Parameters for a generic gas inhalation physiologically-based toxicokinetic model

Description

This function initializes the parameters needed for the model 'gas_pbtk', for example solve_gas_pbtk. Chemical- and species-specific model parameters are generated. These include tissue:plasma partition coefficients via Schmitt (2008)'s method as modified by Pearce et al. (2017). Organ volumes and flows are retrieved from table physiology.data). This model was first described by Linakis et al. (2020).

Usage

parameterize_gas_pbtk(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  tissuelist = list(liver = c("liver"), kidney = c("kidney"), lung = c("lung"), gut =
    c("gut")),
  force.human.clint.fup = FALSE,
  clint.pvalue.threshold = 0.05,
  adjusted.Funbound.plasma = TRUE,
  adjusted.Clint = TRUE,
  regression = TRUE,
  vmax = 0,
  km = 1,
  exercise = FALSE,
  fR = 12,
  VT = 0.75,
  VD = 0.15,
  suppress.messages = FALSE,
  minimum.Funbound.plasma = 1e-04,
  Caco2.options = NULL,
  ...
)

Arguments

chem.cas

Either the chemical name or the CAS number must be specified.

chem.name

Either the chemical name or the CAS number must be specified.

dtxsid

EPA's DSSTox Structure ID (https://comptox.epa.gov/dashboard) the chemical must be identified by either CAS, name, or DTXSIDs

species

Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").

default.to.human

Substitutes missing animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma).

tissuelist

Specifies compartment names and tissues groupings. Remaining tissues in tissue.data are lumped in the rest of the body. However, solve_pbtk only works with the default parameters.

force.human.clint.fup

Forces use of human values for hepatic intrinsic clearance and fraction of unbound plasma if true.

clint.pvalue.threshold

Hepatic clearance for chemicals where the in vitro clearance assay result has a p-values greater than the threshold are set to zero.

adjusted.Funbound.plasma

Uses Pearce et al. (2017) lipid binding adjustment for Funbound.plasma (which impacts partition coefficients) when set to TRUE (Default).

adjusted.Clint

Uses Kilford et al. (2008) hepatocyte incubation binding adjustment for Clint when set to TRUE (Default).

regression

Whether or not to use the regressions in calculating partition coefficients.

vmax

Michaelis-Menten vmax value in reactions/min

km

Michaelis-Menten concentration of half-maximal reaction velocity in desired output concentration units.

exercise

Logical indicator of whether to simulate an exercise-induced heightened respiration rate

fR

Respiratory frequency (breaths/minute), used especially to adjust breathing rate in the case of exercise. This parameter, along with VT and VD (below) gives another option for calculating Qalv (Alveolar ventilation) in case pulmonary ventilation rate is not known

VT

Tidal volume (L), to be modulated especially as part of simulating the state of exercise

VD

Anatomical dead space (L), to be modulated especially as part of simulating the state of exercise

suppress.messages

Whether or not the output messages are suppressed.

minimum.Funbound.plasma

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).

Caco2.options

A list of options to use when working with Caco2 apical to basolateral data Caco2.Pab, default is Caco2.options = list(Caco2.Pab.default = 1.6, Caco2.Fabs = TRUE, Caco2.Fgut = TRUE, overwrite.invivo = FALSE, keepit100 = FALSE). Caco2.Pab.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. See get_fabsgut for further details.

...

Other parameters

Value

BW

Body Weight, kg.

Clint

Hepatic intrinsic clearance, uL/min/10^6 cells

Clint.dist

Distribution of hepatic intrinsic clearance values (median, lower 95th, upper 95th, p value)

Clmetabolismc

Hepatic Clearance, L/h/kg BW.

Fabsgut

Fraction of the oral dose absorbed, i.e. the fraction of the dose that enters the gut lumen.

Fhep.assay.correction

The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al. (2008)

Funbound.plasma

Fraction of chemical unbound to plasma.

Funbound.plasma.adjustment

Fraction unbound to plasma adjusted as described in Pearce et al. 2017

Funbound.plasma.dist

Distribution of fraction unbound to plasma (median, lower 95th, upper 95th)

hematocrit

Percent volume of red blood cells in the blood.

Kblood2air

Ratio of concentration of chemical in blood to air

Kgut2pu

Ratio of concentration of chemical in gut tissue to unbound concentration in plasma.

kgutabs

Rate that chemical enters the gut from gutlumen, 1/h.

Kkidney2pu

Ratio of concentration of chemical in kidney tissue to unbound concentration in plasma.

Kliver2pu

Ratio of concentration of chemical in liver tissue to unbound concentration in plasma.

Klung2pu

Ratio of concentration of chemical in lung tissue to unbound concentration in plasma.

km

Michaelis-Menten concentration of half-maximal activity

Kmuc2air

Mucus to air partition coefficient

Krbc2pu

Ratio of concentration of chemical in red blood cells to unbound concentration in plasma.

Krest2pu

Ratio of concentration of chemical in rest of body tissue to unbound concentration in plasma.

kUrtc

Unscaled upper respiratory tract uptake parameter (L/h/kg^0.75)

liver.density

Density of liver in g/mL

MA

phospholipid:water distribution coefficient, membrane affinity

million.cells.per.gliver

Millions cells per gram of liver tissue.

MW

Molecular Weight, g/mol.

pKa_Accept

compound H association equilibrium constant(s)

pKa_Donor

compound H dissociation equilibirum constant(s)

Pow

octanol:water partition coefficient (not log transformed)

Qalvc

Unscaled alveolar ventilation rate (L/h/kg^0.75)

Qcardiacc

Cardiac Output, L/h/kg BW^3/4.

Qgfrc

Glomerular Filtration Rate, L/h/kg BW^0.75, volume of fluid filtered from kidney and excreted.

Qgutf

Fraction of cardiac output flowing to the gut.

Qkidneyf

Fraction of cardiac output flowing to the kidneys.

Qliverf

Fraction of cardiac output flowing to the liver.

Qlungf

Fraction of cardiac output flowing to lung tissue.

Qrestf

Fraction of blood flow to rest of body

Rblood2plasma

The ratio of the concentration of the chemical in the blood to the concentration in the plasma from available_rblood2plasma.

Vartc

Volume of the arteries per kg body weight, L/kg BW.

Vgutc

Volume of the gut per kg body weight, L/kg BW.

Vkidneyc

Volume of the kidneys per kg body weight, L/kg BW.

Vliverc

Volume of the liver per kg body weight, L/kg BW.

Vlungc

Volume of the lungs per kg body weight, L/kg BW.

vmax

Michaelis-Menten maximum reaction velocity (1/min)

Vmucc

Unscaled mucosal volume (L/kg BW^0.75

Vrestc

Volume of the rest of the body per kg body weight, L/kg BW.

Vvenc

Volume of the veins per kg body weight, L/kg BW.

Author(s)

Matt Linakis, Robert Pearce, John Wambaugh

References

Linakis MW, Sayre RR, Pearce RG, Sfeir MA, Sipes NS, Pangburn HA, Gearhart JM, Wambaugh JF (2020). “Development and evaluation of a high-throughput inhalation model for organic chemicals.” Journal of exposure science & environmental epidemiology, 30(5), 866–877.

Schmitt W (2008). “General approach for the calculation of tissue to plasma partition coefficients.” Toxicology in vitro, 22(2), 457–467.

Pearce RG, Setzer RW, Davis JL, Wambaugh JF (2017). “Evaluation and calibration of high-throughput predictions of chemical distribution to tissues.” Journal of pharmacokinetics and pharmacodynamics, 44, 549–565.

Kilford PJ, Gertz M, Houston JB, Galetin A (2008). “Hepatocellular binding of drugs: correction for unbound fraction in hepatocyte incubations using microsomal binding or drug lipophilicity data.” Drug Metabolism and Disposition, 36(7), 1194–1197.

See Also

solve_gas_pbtk

apply_clint_adjustment

predict_partitioning_schmitt

available_rblood2plasma

calc_kair

tissue.data

physiology.data

get_clint

get_fup

get_physchem_param

Examples

parameters <- parameterize_gas_pbtk(chem.cas='129-00-0')

parameters <- parameterize_gas_pbtk(chem.name='pyrene',species='Rat')

parameterize_gas_pbtk(chem.cas = '56-23-5')

parameters <- parameterize_gas_pbtk(chem.name='Carbon tetrachloride',species='Rat')

# Change the tissue lumping:
compartments <- list(liver=c("liver"),fast=c("heart","brain","muscle","kidney"),
                      lung=c("lung"),gut=c("gut"),slow=c("bone"))
parameterize_gas_pbtk(chem.name="Bisphenol a",species="Rat",default.to.human=TRUE,
                   tissuelist=compartments)