parameterize_1comp: Parameters for a one compartment (empirical) toxicokinetic model

Description

This function initializes the parameters needed in the function solve_1comp. Volume of distribution is estimated by using a modified Schmitt (2008) method to predict tissue particition coefficients (Pearce et al., 2017) and then lumping the compartments weighted by tissue volume:

Usage

parameterize_1comp(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  adjusted.Funbound.plasma = TRUE,
  adjusted.Clint = TRUE,
  regression = TRUE,
  restrictive.clearance = TRUE,
  well.stirred.correction = TRUE,
  suppress.messages = FALSE,
  clint.pvalue.threshold = 0.05,
  minimum.Funbound.plasma = 1e-04,
  class.exclude = TRUE,
  physchem.exclude = TRUE,
  Caco2.options = list(),
  ...
)

Value

Vdist: Volume of distribution, units of L/kg BW.
Fabsgut: Fraction of the oral dose absorbed and surviving gut metabolism, i.e. the fraction of the dose that enters the gutlumen.
kelim: Elimination rate, units of 1/h.
hematocrit: Percent volume of red blood cells in the blood.
Fabsgut: Fraction of the oral dose absorbed, i.e. the fraction of the dose that enters the gutlumen.
Fhep.assay.correction: The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al. (2008)
kelim: Elimination rate, units of 1/h.
hematocrit: Percent volume of red blood cells in the blood.
kgutabs: Rate chemical is absorbed, 1/h.
million.cells.per.gliver: Millions cells per gram of liver tissue.
MW: Molecular Weight, g/mol.
Rblood2plasma: The ratio of the concentration of the chemical in the blood to the concentration in the plasma. Not used in calculations but included for the conversion of plasma outputs.
hepatic.bioavailability: Fraction of dose remaining after first pass clearance, calculated from the corrected well-stirred model.
BW: Body Weight, kg.

Arguments

chem.cas: Chemical Abstract Services Registry Number (CAS-RN) -- the chemical must be identified by either CAS, name, or DTXISD
chem.name: Chemical name (spaces and capitalization ignored) -- the chemical must be identified by either CAS, name, or DTXISD
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 rat values with human values if true.
adjusted.Funbound.plasma: Uses Pearce et al. (2017) lipid binding adjustment for Funbound.plasma (which impacts volume of distribution) 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 in volume of distribution calculation.
restrictive.clearance: In calculating elimination rate and hepatic bioavailability, protein binding is not taken into account (set to 1) in liver clearance if FALSE.
well.stirred.correction: Uses correction in calculation of hepatic clearance for well-stirred model if TRUE. This assumes clearance relative to amount unbound in whole blood instead of plasma, but converted to use with plasma concentration.
suppress.messages: Whether or not to suppress messages.
clint.pvalue.threshold: Hepatic clearance for chemicals where the in vitro clearance assay result has a p-value greater than the threshold are set to zero.
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).
class.exclude: Exclude chemical classes identified as outside of domain of applicability by relevant modelinfo_[MODEL] file (default TRUE).
physchem.exclude: Exclude chemicals on the basis of physico-chemical properties (currently only Henry's law constant) as specified by the relevant modelinfo_[MODEL] file (default TRUE).
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_fbio for further details.
...: Additional arguments, not currently used.

Author

John Wambaugh and Robert Pearce

Details

V_d,steady-state = Sum over all tissues (K_i * V_i) + V_plasma

where K_i is the tissue:unbound plasma concentration partition coefficient for tissue i.

Because this model does not simulate exhalation, inhalation, and other processes relevant to volatile chemicals, this model is by default restricted to chemicals with a logHenry's Law Constant less than that of Acetone, a known volatile chemical. That is, chemicals with logHLC > -4.5 (Log10 atm-m3/mole) are excluded. Volatility is not purely determined by the Henry's Law Constant, therefore this chemical exclusion may be turned off with the argument "physchem.exclude = FALSE". Similarly, per- and polyfluoroalkyl substances (PFAS) are excluded by default because the transporters that often drive PFAS toxicokinetics are not included in this model. However, PFAS chemicals can be included with the argument "class.exclude = FALSE".

References

pearce2017httkhttk

schmitt2008generalhttk

pearce2017evaluationhttk

kilford2008hepatocellularhttk

Examples

Run this code


# \donttest{
 parameters1 <- parameterize_1comp(chem.name='Bisphenol-A',species='Rat')
 parameters2 <- parameterize_1comp(chem.cas='80-05-7',
                                  restrictive.clearance=FALSE,
                                  species='rabbit',
                                  default.to.human=TRUE)
# The following will not work because Diquat dibromide monohydrate's 
# Henry's Law Constant (-3.912) is higher than that of Acetone (~-4.5):
try(parameters3 <- parameterize_1comp(chem.cas = "6385-62-2"))
# However, we can turn off checking for phys-chem properties, since we know
# that  Diquat dibromide monohydrate is not too volatile:
parameters3 <- parameterize_1comp(chem.cas = "6385-62-2",
                                  physchem.exclude = FALSE)
out <- solve_1comp(parameters=parameters1, days=1)
# }

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