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#' solve_gas_pbtk
#'
#' This function solves for the amounts or concentrations of a chemical
#' in different tissues as functions of time as a result of inhalation
#' exposure to an ideal gas.
#'
#' The default dosing scheme involves a specification of the start time
#' of exposure (exp.start.time), the concentration of gas inhaled (exp.conc),
#' the period of a cycle of exposure and non-exposure (period), the
#' duration of the exposure during that period (exp.duration), and the total
#' days simulated. Together,these arguments determine the "forcings" passed to
#' the ODE integrator. Forcings can also be specified manually, or effectively
#' turned off by setting exposure concentration to zero, if the user prefers to
#' simulate dosing by other means.
#'
#' The "forcings" object is configured to be passed to the integrator with,
#' at the most, a basic unit conversion among ppmv, mg/L, and uM. No scaling by
#' BW is set to be performed on the forcings series.
#'
#' Note that the model parameters have units of hours while the model output is
#' in days.
#'
#' Default NULL value for doses.per.day solves for a single dose.
#'
#' The compartments used in this model are the gut lumen, gut, liver, kidneys,
#' veins, arteries, lungs, and the rest of the 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.
#'
#' Model Figure from \insertCite{linakis2020development}{httk}:
#' \if{html}{\figure{gaspbtk.jpg}{options: width="100\%" alt="Figure: Gas PBTK
#' Model Schematic"}}
#' \if{latex}{\figure{gaspbtk.pdf}{options: width=12cm alt="Figure: Gas PBTK
#' Model Schematic"}}
#'
#' Model parameters are named according to the following convention:\tabular{lrrrr}{
#' prefix \tab suffic \tab Meaning \tab units \cr
#' K \tab \tab Partition coefficient for tissue to free plasma \ tab unitless \cr
#' V \tab \tab Volume \tab L \cr
#' Q \tab \tab Flow \tab L/h \cr
#' k \tab \tab Rate \tab 1/h \cr
#' \tab c \tab Parameter is proportional to body weight \tab 1 / kg for volumes
#' and 1/kg^(3/4) for flows \cr}
#'
#' When species is specified but chemical-specific in vitro data are not
#' available, the function uses the appropriate physiological data (volumes and
#' flows) but default.to.human = TRUE must be used to substitute human
#' fraction unbound, partition coefficients, and intrinsic hepatic clearance.
#'
#'
#' @param chem.name Either the chemical name, CAS number, or the parameters
#' must be specified.
#'
#' @param chem.cas Either the chemical name, CAS number, or the parameters must
#' be specified.
#'
#' @param dtxsid EPA's DSSTox Structure ID (\url{https://comptox.epa.gov/dashboard})
#' the chemical must be identified by either CAS, name, or DTXSIDs
#'
#' @param parameters Chemical parameters from parameterize_gas_pbtk (or other
#' bespoke) function, overrides chem.name and chem.cas.
#'
#' @param times Optional time sequence for specified number of days. Dosing
#' sequence begins at the beginning of times.
#'
#' @param days Length of the simulation.
#'
#' @param tsteps The number of time steps per hour.
#'
#' @param daily.dose Total daily dose
#'
#' @param doses.per.day Number of doses per day.
#'
#' @param dose Amount of a single dose
#'
#' @param dosing.matrix Vector of dosing times or a matrix consisting of two
#' columns or rows named "dose" and "time" containing the time and amount of
#' each dose.
#'
#' @param forcings Manual input of 'forcings' data series argument for ode
#' integrator. If left unspecified, 'forcings' defaults to NULL, and then other
#' input parameters (see exp.start.time, exp.conc, exp.duration, and period)
#' provide the necessary information to assemble a forcings data series.
#'
#' @param exp.start.time Start time in specifying forcing exposure series,
#' default 0.
#'
#' @param exp.conc Specified inhalation exposure concentration for use in
#' assembling "forcings" data series argument for integrator. Defaults to
#' units of ppmv.
#'
#' @param period For use in assembling forcing function data series 'forcings'
#' argument, specified in hours
#'
#' @param exp.duration For use in assembling forcing function data
#' series 'forcings' argument, specified in hours
#'
#' @param initial.values Vector containing the initial concentrations or
#' amounts of the chemical in specified tissues with units corresponding to
#' those specified for the model outputs. Default values are zero.
#'
#' @param plots Plots all outputs if true.
#'
#' @param suppress.messages Whether or not the output message is suppressed.
#'
#' @param species Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or
#' default "Human").
#'
#' @param iv.dose Simulates a single i.v. dose if true.
#'
#' @param input.units Input units of interest assigned to dosing, including
#' forcings. Defaults to "ppmv" as applied to the default forcings scheme.
#'
#' @param 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.
#'
#' @param method Method used by integrator (deSolve).
#'
#' @param rtol Argument passed to integrator (deSolve).
#'
#' @param atol Argument passed to integrator (deSolve).
#'
#' @param default.to.human Substitutes missing animal values with human values
#' if true (hepatic intrinsic clearance or fraction of unbound plasma).
#'
#' @param 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.
#'
#' @param recalc.clearance Recalculates the hepatic clearance
#' (Clmetabolism) with new million.cells.per.gliver parameter.
#'
#' @param adjusted.Funbound.plasma Uses adjusted Funbound.plasma when set to
#' TRUE along with partition coefficients calculated with this value.
#'
#' @param regression Whether or not to use the regressions in calculating
#' partition coefficients.
#'
#' @param restrictive.clearance Protein binding not taken into account (set to
#' 1) in liver clearance if FALSE.
#'
#' @param 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).
#'
#' @param monitor.vars Which variables are returned as a function of time.
#' Defaults value of NULL provides "Cgut", "Cliver", "Cven", "Clung", "Cart",
#' "Crest", "Ckidney", "Cplasma", "Calv", "Cendexh", "Cmixexh", "Cmuc",
#' "Atubules", "Ametabolized", "AUC"
#'
#' @param vmax Michaelis-Menten vmax value in reactions/min
#'
#' @param km Michaelis-Menten concentration of half-maximal reaction velocity
#' in desired output concentration units.
#'
#' @param exercise Logical indicator of whether to simulate an exercise-induced
#' heightened respiration rate
#'
#' @param 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
#'
#' @param VT Tidal volume (L), to be modulated especially as part of simulating
#' the state of exercise
#'
#' @param VD Anatomical dead space (L), to be modulated especially as part of
#' simulating the state of exercise
#'
#' @param ... Additional arguments passed to the integrator.
#'
#' @return 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.
#'
#' @author Matt Linakis, John Wambaugh, Mark Sfeir, Miyuki Breen
#'
#' @references
#' \insertRef{linakis2020development}{httk}
#'
#' \insertRef{pearce2017httk}{httk}
#'
#' @keywords Solve
#'
#' @seealso \code{\link{solve_model}}
#'
#' @seealso \code{\link{parameterize_gas_pbtk}}
#'
#' @examples
#' \donttest{
#'
#' solve_gas_pbtk(chem.name = 'pyrene', exp.conc = 1, period = 24, expduration = 24)
#'
#' out <- solve_gas_pbtk(chem.name='pyrene',
#' exp.conc = 0, doses.per.day = 2,
#' daily.dose = 3, input.units = "umol",
#' days=2.5,
#' plots=TRUE, initial.values=c(Aven=20))
#'
#' out <- solve_gas_pbtk(chem.name = 'pyrene', exp.conc = 3,
#' period = 24, days=2.5,
#' exp.duration = 6, exercise = TRUE)
#'
#' params <- parameterize_gas_pbtk(chem.cas="80-05-7")
#' solve_gas_pbtk(parameters=params, days=2.5)
#'
#' # Oral dose with exhalation as a route of elimination:
#' out <- solve_gas_pbtk(chem.name = 'bisphenol a', exp.conc = 0, dose=100,
#' days=2.5, input.units="mg/kg")
#'
#' # Note that different model compartments for this model have different units
#' # and that the final units can be controlled with the output.units argument:
#' head(solve_gas_pbtk(chem.name="lindane", days=2.5))
#' # Convert all compartment units to mg/L:
#' head(solve_gas_pbtk(chem.name="lindane", days=2.5, output.units="mg/L"))
#' # Convert just the plasma to mg/L:
#' head(solve_gas_pbtk(chem.name="lindane", days=2.5,
#' output.units=list(Cplasma="mg/L")))
#' }
#'
#' @export solve_gas_pbtk
#'
#' @importFrom Rdpack reprompt
solve_gas_pbtk <- function(chem.name = NULL,
chem.cas = NULL,
dtxsid = NULL,
parameters=NULL,
times=NULL,
days=10,
tsteps = 4, #tsteps is number of steps per hour
daily.dose = NULL,
doses.per.day = NULL,
dose = NULL,
dosing.matrix = NULL,
forcings = NULL,
exp.start.time = 0, #default starting time in specifying forcing exposure
exp.conc = 1, #default exposure concentration for forcing data series
period = 24,
exp.duration = 12,
initial.values=NULL,
plots=FALSE,
suppress.messages=FALSE,
species="Human",
iv.dose=FALSE,
input.units = "ppmv", # assume input units are ppmv with updated inhalation model
# input.units = "uM",
output.units=NULL,
method="lsoda",rtol=1e-8,atol=1e-12,
default.to.human=FALSE,
recalc.blood2plasma=FALSE,
recalc.clearance=FALSE,
adjusted.Funbound.plasma=TRUE,
regression=TRUE,
restrictive.clearance = TRUE,
minimum.Funbound.plasma=0.0001,
monitor.vars=NULL,
vmax = 0,
km = 1,
exercise = FALSE,
fR = 12,
VT = 0.75,
VD = 0.15,
...)
{
#Screen against error in user's specification of forcing function timing
if (exp.duration > period){
stop("Argument 'exp.duration' should be smaller than its subsuming argument,
'period', which together are set to specify a simple cyclic pattern of
inhalation exposure and rest in the default case.")
}
# Screen whether exposure and dosing are both indicated to occur
if((exp.conc!=0 | is.null(forcings)==FALSE) & (is.null(dose)==FALSE | is.null(daily.dose)==FALSE)){
stop("Currently, 'httk' only evaluates the model using the exposure or dose",
" route but not both simultaneously. If exposure is the goal, then",
" set dose and/or daily.dose to NULL. If dose is the goal, then",
" set exp.conc to 0.")
}
# Obtain the appropriate route for compound exposure/dosing.
if(exp.conc!=0 | is.null(forcings)==FALSE){
route <- "inhalation"
# if(input.units!="ppmv"){
# stop("The ",input.units," units are not appropriate for the exposure route. ",
# "Review input units for doses and update argument. ",
# "Several suggestions 'umol', 'mg', or an alternative input.")
# }
}else if(is.null(dose)==FALSE | is.null(daily.dose)==FALSE){
route <- ifelse(iv.dose,yes = "iv",no = "oral")
if(input.units=="ppmv"){
stop("The 'ppmv' units are not appropriate for the dosing routes. ",
"Review input units for doses and update argument. ",
"Several suggestions 'umol', 'mg', or an alternative input.")
}
}
#Look up the chemical name/CAS to get some info about the chemical in
#question and screen it for relevance of its logHenry value. Should not
#be necessary if user manually specifies 'parameters'
if (is.null(parameters)){
out <- get_chem_id(
chem.cas=chem.cas,
chem.name=chem.name,
dtxsid=dtxsid)
chem.cas <- out$chem.cas
chem.name <- out$chem.name
dtxsid <- out$dtxsid
#If value of Henry's law constant associated with queried chemical is smaller
#than that of glycerol, generally considered non-volatile, issue warning
#message:
#get associated logHenry value and compare against glycerol's value, obtained
#from EPA dashboard
logHenry = chem.physical_and_invitro.data[chem.cas,'logHenry']
if (is.na(logHenry)) stop (
"Henry's constant is not available for this compound")
glycerol_logHenry = -7.80388
if (logHenry <= glycerol_logHenry){
warning("Henry's constant, as a measure of volatility, is smaller for the
queried chemical than for glycerol, a chemical generally considered
nonvolatile. Please proceed after having considered whether the inhalation
exposure route is nonetheless relevant.")
}
}
#Only generate the forcings if other dosing metrics are null; they're not
#designed to work together in a very meaningful way
if (is.null(dosing.matrix) & is.null(doses.per.day) & is.null(forcings))
{
if (exp.duration > period){
stop('If not specifying \'dose.matrix\' data series explicitly,
additional arguments are needed to generate a \'dose.matrix\' argument
with a cyclic exposure pattern across the simulation:
exp.conc, period, exp.start.time, exp.duration, and days simulated.')
}
period <- period/24 #convert time period in hours to days
exp.duration <- exp.duration/24 #convert exposure duration in hours to days
#Assemble function for initializing 'forcings' argument data series with
#certain periodicity and exposure concentration in default case, used if
#the 'forcings' argument is not otherwise specified.
forcings_gen <- function(exp.conc, period, exp.start.time, exp.duration, days) {
#Provide for case in which forcing functionality is effectively turned off
if (exp.conc == 0) {
conc.matrix = NULL
} else {
Nrep <- ceiling((days - exp.start.time)/period)
times <- rep(c(exp.start.time, exp.duration), Nrep) + rep(period * (0:(Nrep - 1)), rep(2, Nrep))
forcing_values <- rep(c(exp.conc,0), Nrep)
conc.matrix = cbind(times,forcing_values)
}
return(conc.matrix)
}
forcings = forcings_gen(exp.conc, period, exp.start.time = 0, exp.duration, days)
}
#Comment out tentative alternate scheme to forcings for now
###
#Nrep <- ceiling((days - exp.start.time)/period)
# We want the start and stop timeS:
#time <- sort(c(period * (0:(Nrep - 1)), # Start times
#period * (0:(Nrep - 1))+exp.duration)) # End times
#dose <- rep(c(exp.conc,0), Nrep)
#dosing.matrix = cbind(dose,time)
###
#Now make call to solve_model with gas model specific arguments configured
out <- solve_model(
chem.name = chem.name,
chem.cas = chem.cas,
dtxsid=dtxsid,
times=times,
parameters=parameters,
model="gas_pbtk",
route=route,
# route='inhalation',
dosing=list(
initial.dose=dose,
dosing.matrix=dosing.matrix,
daily.dose=daily.dose,
doses.per.day=doses.per.day,
forcings=forcings),
days=days,
tsteps = tsteps, # tsteps is number of steps per hour
initial.values=initial.values,
plots=plots,
monitor.vars=monitor.vars,
suppress.messages=suppress.messages,
species=species,
input.units=input.units,
output.units=output.units,
method=method,rtol=rtol,atol=atol,
recalc.blood2plasma=recalc.blood2plasma,
recalc.clearance=recalc.clearance,
adjusted.Funbound.plasma=adjusted.Funbound.plasma,
parameterize.arg.list = list(
regression=regression,
default.to.human=default.to.human,
restrictive.clearance = restrictive.clearance,
exercise = exercise,
vmax = vmax,
km = km,
fR = fR,
VT = VT,
VD = VD),
minimum.Funbound.plasma=minimum.Funbound.plasma,
...)
return(out)
}
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