calc_mc_tk: Conduct multiple TK simulations using Monte Carlo

In httk: High-Throughput Toxicokinetics

Conduct multiple TK simulations using Monte Carlo

Description

This function finds the analytical steady state plasma concentration(from calc_analytic_css) using a monte carlo simulation (monte_carlo).

Usage

calc_mc_tk(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  parameters = NULL,
  samples = 1000,
  species = "Human",
  suppress.messages = FALSE,
  model = "pbtk",
  httkpop = TRUE,
  httkpop.dt = NULL,
  invitrouv = TRUE,
  calcrb2p = TRUE,
  censored.params = list(),
  vary.params = list(),
  return.samples = FALSE,
  tissue = NULL,
  output.units = "mg/L",
  solvemodel.arg.list = list(times = c(0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5)),
  Caco2.options = list(),
  invitro.mc.arg.list = NULL,
  httkpop.generate.arg.list = list(method = "direct resampling"),
  convert.httkpop.arg.list = NULL,
  parameterize.arg.list = NULL,
  return.all.sims = FALSE
)

Arguments

chem.cas	Either the CAS number, parameters, or the chemical name must be specified.
chem.name	Either the chemical parameters, 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
parameters	Parameters from parameterize_steadystate. Not used with httkpop model.
samples	Number of samples generated in calculating quantiles.
species	Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human"). Species must be set to "Human" to run httkpop model.
suppress.messages	Whether or not to suppress output message.
model	Model used in calculation: 'pbtk' for the multiple compartment model,'3compartment' for the three compartment model, '3compartmentss' for the three compartment steady state model, and '1compartment' for one compartment model. This only applies when httkpop=TRUE and species="Human", otherwise '3compartmentss' is used.
httkpop	Whether or not to use population generator and sampler from httkpop. This is overwrites censored.params and vary.params and is only for human physiology. Species must also be set to 'Human'.
httkpop.dt	A data table generated by httkpop_generate. This defaults to NULL, in which case httkpop_generate is called to generate this table.
invitrouv	Logical to indicate whether to include in vitro parameters in uncertainty and variability analysis
calcrb2p	Logical determining whether or not to recalculate the chemical ratio of blood to plasma
censored.params	The parameters listed in censored.params are sampled from a normal distribution that is censored for values less than the limit of detection (specified separately for each parameter). This argument should be a list of sub-lists. Each sublist is named for a parameter in "parameters" and contains two elements: "CV" (coefficient of variation) and "LOD" (limit of detection, below which parameter values are censored. New values are sampled with mean equal to the value in "parameters" and standard deviation equal to the mean times the CV. Censored values are sampled on a uniform distribution between 0 and the limit of detection. Not used with httkpop model.
vary.params	The parameters listed in vary.params are sampled from a normal distribution that is truncated at zero. This argument should be a list of coefficients of variation (CV) for the normal distribution. Each entry in the list is named for a parameter in "parameters". New values are sampled with mean equal to the value in "parameters" and standard deviation equal to the mean times the CV. Not used with httkpop model.
return.samples	Whether or not to return the vector containing the samples from the simulation instead of the selected quantile.
tissue	Desired steady state tissue conentration.
output.units	Plasma concentration units, either uM or default mg/L.
solvemodel.arg.list	Additional arguments ultimately passed to solve_model
Caco2.options	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.
invitro.mc.arg.list	List of additional parameters passed to invitro_mc
httkpop.generate.arg.list	Additional parameters passed to httkpop_generate.
convert.httkpop.arg.list	Additional parameters passed to the convert_httkpop_* function for the model.
parameterize.arg.list	Additional parameters passed to the parameterize_* function for the model.
return.all.sims	Logical indicating whether to return the results of all simulations, in addition to the default toxicokinetic statistics

Details

The Monte Carlo methods used here were recently updated and described by Breen et al. (submitted).

All arguments after httkpop only apply if httkpop is set to TRUE and species to "Human".

When species is specified as rabbit, dog, or mouse, the function uses the appropriate physiological data(volumes and flows) but substitues human fraction unbound, partition coefficients, and intrinsic hepatic clearance.

Tissue concentrations are calculated for the pbtk model with oral infusion dosing. All tissues other than gut, liver, and lung are the product of the steady state plasma concentration and the tissue to plasma partition coefficient.

The six sets of plausible in vitro-in vivo extrpolation (IVIVE) assumptions identified by Honda et al. (2019) (\Sexpr[results=rd]{tools:::Rd_expr_doi("10.1371/journal.pone.0217564")}) are:

	in vivo Conc.	Metabolic Clearance	Bioactive Chemical Conc.	TK Statistic Used*
Honda1	Veinous (Plasma)	Restrictive	Free	Mean Conc.
Honda2	Veinous	Restrictive	Free	Max Conc.
Honda3	Veinous	Non-restrictive	Total	Mean Conc.
Honda4	Veinous	Non-restrictive	Total	Max Conc.
Honda5	Target Tissue	Non-restrictive	Total	Mean Conc.
Honda6	Target Tissue	Non-restrictive	Total	Max Conc.

*Assumption is currently ignored because analytical steady-state solutions are currently used by this function.

Value

If return.all.sims == FALSE (default) a list with:

means	The mean concentration for each model compartment as a function of time across the Monte Carlo simulation
sds	The standard deviation for each model compartment as a function of time across the Monte Carlo simulation

If return.all.sums == TRUE then a list is returned with:

stats	The list of means and sds from return.all.sums=FALSE
sims	The concentration vs. time results for each compartment for every (samples) set of parameters in the Monte Carlo simulation

Author(s)

John Wambaugh

See Also

create_mc_samples

Examples

NSAMP <- 50
chemname="Abamectin"
times<- c(0,0.25,0.5,0.75,1,1.5,2,2.5,3,4,5)
age.ranges <- seq(6,80,by=10)
forward <- NULL
for (age.lower in age.ranges)
{
  label <- paste("Ages ",age.lower,"-",age.lower+4,sep="")
  set.seed(1234)
  forward[[label]] <- calc_mc_tk(
                        chem.name=chemname,
                        samples=NSAMP,
                        httkpop.generate.arg.list=list(
                          method="d",
                          agelim_years = c(age.lower, age.lower+9)),
                        solvemodel.arg.list = list(
                          times=times))
}

httk documentation built on Sept. 11, 2024, 9:32 p.m.