solve_fetal_pbtk: Solve_fetal_PBTK

Description

This function solves for the amounts or concentrations in uM of a chemical in different tissues of a maternofetal system as functions of time based on the dose and dosing frequency.

Usage

solve_fetal_pbtk(
  chem.name = NULL,
  chem.cas = NULL,
  dtxsid = NULL,
  times = seq(13 * 7, 40 * 7, 1),
  parameters = NULL,
  days = NULL,
  species = "human",
  tsteps = 1,
  dose = NULL,
  dosing.matrix = NULL,
  daily.dose = NULL,
  doses.per.day = NULL,
  initial.values = NULL,
  plots = FALSE,
  suppress.messages = FALSE,
  iv.dose = FALSE,
  input.units = "mg/kg",
  output.units = NULL,
  physchem.exclude = TRUE,
  class.exclude = TRUE,
  recalc.blood2plasma = FALSE,
  recalc.clearance = FALSE,
  adjusted.Funbound.plasma = TRUE,
  regression = TRUE,
  restrictive.clearance = TRUE,
  minimum.Funbound.plasma = 1e-04,
  monitor.vars = NULL,
  Caco2.options = list(),
  atol = 1e-06,
  rtol = 1e-06,
  ...
)

Value

A matrix of class deSolve with a column for time(in days), each compartment, the area under the curve, and plasma concentration and a row for each time point.

Arguments

chem.name: Either the chemical name, CAS number, or the parameters must be specified.
chem.cas: Either the chemical name, CAS number, or the parameters must be specified.
dtxsid: EPA's DSSTox Structure ID (http://comptox.epa.gov/dashboard) the chemical must be identified by either CAS, name, or DTXSIDs
times: Optional time sequence in days. Dosing sequence begins at the beginning of times. Default is from 13th week of pregnancy to 40th due to data constraints.
parameters: Chemical parameters from parameterize_fetal_pbtk function, overrides chem.name and chem.cas.
days: Length of the simulation.
species: Included for compatibility with other functions, but the model will not run for non-human species (default "Human").
tsteps: The number time steps per hour. Default of 4.
dose: Amount of a single, initial oral dose in mg/kg BW.
dosing.matrix: A matrix of either one column (or row) with a set of dosing times or with two columns (or rows) correspondingly named "dose" and "time" containing the time and amount, in mg/kg BW, of each dose.
daily.dose: Total daily dose, mg/kg BW.
doses.per.day: Number of doses per day.
initial.values: Vector containing the initial concentrations or amounts of the chemical in specified tissues with units corresponding to compartment.units. Defaults are zero.
plots: Plots all outputs if true.
suppress.messages: Whether or not the output message is suppressed.
iv.dose: Simulates a single i.v. dose if true.
input.units: Input units of interest assigned to dosing, defaults to mg/kg BW
output.units: A named vector of output units expected for the model results. Default, NULL, returns model results in units specified in the 'modelinfo' file. See table below for details.
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).
class.exclude: Exclude chemical classes identified as outside of domain of applicability by relevant modelinfo_[MODEL] file (default TRUE).
recalc.blood2plasma: Recalculates the ratio of the amount of chemical in the blood to plasma using the input parameters, calculated with hematocrit, Funbound.plasma, and Krbc2pu.
recalc.clearance: Recalculates the the hepatic clearance (Clmetabolism) with new million.cells.per.gliver parameter.
adjusted.Funbound.plasma: Uses adjusted Funbound.plasma when set to TRUE along with partition coefficients calculated with this value.
regression: Whether or not to use the regressions in calculating partition coefficients.
restrictive.clearance: Protein binding not taken into account (set to 1) in liver clearance if FALSE.
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).
monitor.vars: Which variables to track by default
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.
atol: Absolute tolerance used by integrator (deSolve) to determine numerical precision-- defaults to 1e-8.
rtol: Relative tolerance used by integrator (deSolve) to determine numerical precision -- defaults to 1e-8.
...: Additional arguments passed to the integrator.

Author

John Wambaugh, Mark Sfeir, and Dustin Kapraun

Details

The stage of pregnancy simulated here begins by default at the 13th week due to a relative lack of data to support parameterization prior, in line with the recommendations of Kapraun et al. 2019 ("Empirical models for anatomical and physiological..."), and ends at the 40th week of pregnancy.

Note that the model parameters have units of hours while the model output is in days. Dose is in mg, not scaled for body weight.

Default NULL value for doses.per.day solves for a single dose.

The maternal compartments used in this model are the gut lumen, gut, liver, venous blood, arterial blood, lung, adipose tissue, kidney, thyroid, and rest of body. A placenta is modeled as a joint organ shared by mother and fetus, through which chemical exchange can occur with the fetus. Fetal compartments include arterial blood, venous blood, kidney, thyroid, liver, lung, gut, brain, and rest of body.

The extra compartments include the amounts or concentrations metabolized by the liver and excreted by the kidneys through the tubules.

AUC is the area under the curve of the plasma concentration.

This gestational model is only parameterized for humans.

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

kapraun2022fetalmodelhttk

Examples

Run this code


# \donttest{
out = solve_fetal_pbtk(chem.name = 'bisphenol a', daily.dose = 1,
doses.per.day = 3)

# With adjustement to fraction unbound plasma for fetus:
fetal_parms_fup_adjusted <- 
  parameterize_fetal_pbtk(chem.name = "triclosan")
head(solve_fetal_pbtk(parameters = fetal_parms_fup_adjusted))
 
# Without adjustement to fraction unbound plasma for fetus:
fetal_parms_fup_unadjusted <-  
  parameterize_fetal_pbtk(chem.name = "triclosan",
                          fetal_fup_adjustment = FALSE)
head(solve_fetal_pbtk(parameters = fetal_parms_fup_unadjusted))

# 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(head(solve_fetal_pbtk(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:
head(solve_fetal_pbtk(chem.cas = "6385-62-2", physchem.exclude = FALSE))

# Try different ways to call the function:
head(solve_fetal_pbtk(chem.cas="80-05-7"))
head(solve_fetal_pbtk(parameters=parameterize_fetal_pbtk(chem.cas="80-05-7")))
# }

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