This function finds the analytical steady state plasma concentration(from calc_analytic_css) using a monte carlo simulation (monte_carlo).
calc_mc_css(chem.cas = NULL, chem.name = NULL, parameters = NULL,
daily.dose = 1, which.quantile = 0.95, species = "Human",
output.units = "mg/L", suppress.messages = F,
model = "3compartmentss",
censored.params = list(Funbound.plasma = list(cv = 0.3, lod = 0.01)),
vary.params = list(BW = 0.3, Vliverc = 0.3, Qgfrc = 0.3,
Qtotal.liverc = 0.3,
million.cells.per.gliver = 0.3, Clint = 0.3),
samples = 1000, return.samples = F, default.to.human = F,
tissue = NULL, well.stirred.correction = T,
adjusted.Funbound.plasma = T, regression = T,
clint.pvalue.threshold = 0.05,
restrictive.clearance = T,
tk.statistic.used = "mean",
IVIVE=NULL,
httkpop = T,
poormetab = T, fup.censor = T,
Clint.vary = T, sigma.factor = 0.3, lod = 0.01,
method = "direct resampling", gendernum = NULL,
agelim_years = NULL, agelim_months = NULL,
weight_category = c("Underweight", "Normal", "Overweight", "Obese"),
gfr_category = c("Normal","Kidney Disease", "Kidney Failure"),
reths = c("Mexican American", "Other Hispanic",
"Non-Hispanic White", "Non-Hispanic Black", "Other"),
physiology.matrix = NULL, parameter.matrix = NULL,
...)Either the chemical parameters, name, or the CAS number must be specified.
Either the CAS number, parameters, or the chemical name must be specified.
Parameters from parameterize_steadystate. Not used with httkpop model.
Total daily dose, mg/kg BW/day.
Which quantile from Monte Carlo simulation is requested. Can be a vector.
Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human"). Species must be set to "Human" to run httkpop model.
Plasma concentration units, either uM or default mg/L.
Whether or not to suppress output message.
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 paramter). 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.
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.
Number of samples generated in calculating quantiles.
Whether or not to return the vector containing the samples from the simulation instead of the selected quantile.
Substitutes missing rat values with human values if true.
Desired steady state tissue conentration.
Uses adjusted Funbound.plasma when set to TRUE along with partition coefficients calculated with this value.
Whether or not to use the regressions in calculating partition coefficients.
If TRUE (default) then the well-stirred correction (Rowland et al., 1973) is used in the calculation of hepatic clearance for the models that do not include flows for first-pass metabolism (currently, 1compartment and 3compartmentss). This assumes clearance relative to amount unbound in whole blood instead of plasma, but converted for use with plasma concentration.
Protein binding not taken into account (set to 1) in liver clearance if FALSE.
Theoreticially either the "mean" or "max"imum (peak) concetrations might be used for IVIVE with some models. Defaults to "mean". Meaningless for the steady-state model (Argument is currently ignored because analytic steady-state solutions are used by this function.).
Honda et al. (submitted) identified six plausible sets of assumptions for in vitro-in vivo extrapolation (IVIVE) assumptions. Argument may be set to "Honda1" through "Honda6". If used, this function overwrites the tissue, restrictive.clearance, and plasma.binding arguments. See Details below for more information.
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'.
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.
TRUE (include poor metabolizers) or FALSE (exclude poor metabolizers)
TRUE (draw Funbound.plasma from a censored
distribution) or FALSE (draw Funbound.plasma from a non-censored
distribution)
The coefficient of variation to use for Clint and
Funbound.plasma distributions. Default value is 0.3.
TRUE (sample Clint values) or FALSE (hold
Clint fixed). Default TRUE. If Clint.vary is FALSE, then
poormetab will have no effect.
The average limit of detection for Funbound.plasma. if
fup.censor == TRUE, the Funbound.plasma distribution will be
censored below lod/2. Default value is 0.01.
The population-generation method to use. Either "virtual individuals" or "direct resampling" (default). Short names may be used: "d" or "dr" for "direct resampling", and "v" or "vi" for "virtual individuals".
Optional: A named list giving the numbers of male and female
individuals to include in the population, e.g. list(Male=100,
Female=100). Default is NULL, meaning both males and females are included,
in their proportions in the NHANES data. If both nsamp and
gendernum are provided, they must agree (i.e., nsamp must be
the sum of gendernum).
Optional: A two-element numeric vector giving the minimum
and maximum ages (in years) to include in the population. Default is
c(0,79). If only a single value is provided, both minimum and maximum ages
will be set to that value; e.g. agelim_years=3 is equivalent to
agelim_years=c(3,3). If agelim_years is provided and
agelim_months is not, agelim_years will override the default
value of agelim_months.
Optional: A two-element numeric vector giving the minimum
and maximum ages (in months) to include in the population. Default is c(0,
959), equivalent to the default agelim_years. If only a single value
is provided, both minimum and maximum ages will be set to that value; e.g.
agelim_months=36 is equivalent to agelim_months=c(36,36). If
agelim_months is provided and agelim_years is not,
agelim_months will override the default values of agelim_years.
Optional: The weight categories to include in the
population. Default is c('Underweight', 'Normal', 'Overweight',
'Obese'). User-supplied vector must contain one or more of these strings.
The kidney function categories to include in the
population. Default is c('Normal','Kidney Disease', 'Kidney Failure')
to include all kidney function levels.
Optional: a character vector giving the races/ethnicities to
include in the population. Default is c('Mexican American','Other
Hispanic','Non-Hispanic White','Non-Hispanic Black','Other'), to include
all races and ethnicities in their proportions in the NHANES data.
User-supplied vector must contain one or more of these strings.
A data table generated by httkpop_generate().
A data table generated by get_httk_params().
Hepatic clearance for chemicals where the in vitro clearance assay result has a p-values greater than the threshold are set to zero.
Additional parameters passed to calc_analytic_css
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. (submitted) 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.
Ring, Caroline L., et al. "Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability." Environment international 106 (2017): 105-118. Honda, Gregory S., et al. "Using the Concordance of In Vitro and In Vivo Data to Evaluate Extrapolation Assumptions", submitted. Rowland, Malcolm, Leslie Z. Benet, and Garry G. Graham. "Clearance concepts in pharmacokinetics." Journal of pharmacokinetics and biopharmaceutics 1.2 (1973): 123-136.
# NOT RUN {
calc_mc_css(chem.name='Bisphenol A',output.units='uM',method='vi',
samples=100,return.samples=TRUE)
calc_mc_css(chem.name='2,4-d',which.quantile=.9,httkpop=FALSE,tissue='heart')
calc_mc_css(chem.cas = "80-05-7", daily.dose = 1, which.quantile = 0.5,
censored.params = list(Funbound.plasma = list(cv = 0.1,
lod = 0.005)),
vary.params = list(BW = 0.15, Vliverc = 0.15, Qgfrc = 0.15,
Qtotal.liverc = 0.15,
million.cells.per.gliver = 0.15, Clint = 0.15),
output.units = "uM", samples = 2000)
params <- parameterize_pbtk(chem.cas="80-05-7")
calc_mc_css(parameters=params,model="pbtk")
# }
# NOT RUN {
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# }
# NOT RUN {
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# }
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