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This patch addresses a number of bugs.
get_fabsgut
create_mc_samples
could not handle argument parameters being a list (as in, parameters=parameterize_steadstate(chem.name=“bisphenola”))calc_css
now explain that function is only applicable to dynamical (time-evolving) models and handles errors with other models (such as 3compartmentss) more gracefullyconvert_units
were actually ppmw. Cannot calculate ppmv without chemical-specific liquid density, which we do not know.armitage_eval
to allow chemical specification by usual arguments chem.name, chem.cas, and DTXSID. Preserved casrn.vector for backward compatibility.armitage_eval
to allow multiple instances of chemicals (no longer using CASRN as row names) – thank you Katie Paul Friedman for suggestionsolve_model
now gives warnings when ignoring elements of dosing for a given model and route (acceptible dosing.params are now specified by the modelinfo_[MODEL].R file)This version accompanies the submission of manuscript Honda et al. “Impact of Gut Permeability on Estimation of Oral Bioavailability for Chemicals in Commerce and the Environment”. Find the analysis scripts on GitHub
calc_css
works for accumulative chemcialsconvert_units
solve_model
is no longer restricted to four significant figurescalc_mc_oral_equiv
) wherein you could not specify the argument parameters to be a table created by create_mc_samples
(thanks Jayme Coyle and Tyler Lalonde)convert_units
to handle multiple molecular weights – this enables convert_mc_oral_equivalent
to take a table of parameters for Monte Carloget_clint
and get_invtroPK_param
to be more informativeinvitrouv=FALSE
(thanks cm16120)load_honda2023
to load QSPR (quantitative structure-property relationship model) predictions for Caco-2 membrane permeability for ~10,000 chemicals – QSPR is optimized to detect low permeability chemicals and therefore predicts only three values (low/medium/high permeability)calc_fbio.oral
, calc_fabs.oral
, and calc_fgut.oral
for calculating systemic bioavailability as Fbio = Fabs Fgut * Fhep* where first-pass hepatic metabolism was already available from calc_hep_bioavailability
.invitro_uv
benchmark_httk
to compare current function of the package against historical performance (stored in data.frame httk.performance
)calc_tkstats
to allow PBTK model to distribute iv dosesload_dawson2021
(thank you Alex Fisher and Mike Tornero!)armitage_eval
to properly convert water solubility from OPERA units)convert_units
, expanding the variety of unit conversions available – it is critical to distringuish between state of matter (liquid vs. gas)get_physchem_param
to be case-insensitivecal_hep_clearance
– Kilford (2008) adjustment now only occurs in parameterization functions* Added new function apply_clint_adjustment
to standardize implementation of adjustment (thanks Todor Antonijevic)calc_ionization
that caused error when argument pH was a vector – impacts Monte Carlo for ionized compoundssolve_model
returned other than requested times when argument times was specified (thanks Kimberly Truong)calc_fup_correction
and apply_fup_adjustment
to consolidate and make uniform application of the Pearce et al. (2017) lipid binding adjustment to in vitro measured fupcalc_dow
for the distribution coefficientcalc_ma
separates membrane affinity calculation from parameterize_schmitt
calc_kair
separates calculation of blood:air, water:air, and mucus:air partition coefficients from parameterize_gas_pbtk
calc_fup_correction
and calc_hep_fu
based on the idea that the in vitro assays are not long enough to reach concentration ratios greater than 1,000,000 to 1calc_analytic_css_pbtk
to reflect Breen et al. (2022) modification to glomerular filtration in the kidneyget_cheminfo
now lists required parameters when chemicals are excluded (thanks Ben Savage)daily.dose
argument to calc_mc_css
(still defaults to 1 mg/kg/day)calc_mc_css
and calc_mc_tk
since now internally using do.call
wherever possible to pass argumentssolve_model
predict_partitioning_schmitt
identifying corresponding equations in Schmitt (2008)class.exclude
to get_cheminfo
– defaults to TRUE
, but if FALSE
then chemical classes are not excluded on the basis of specified modelThis minor update removes UTF-8 characters from the package and changes the calculation of kUrt on line 292 of model_gas_pbtk.c
to reduce vulnerability to machine precision errors.
This version accompanies the submission of the Breen et al. manuscript “Simulating Toxicokinetic Variability to Identify Susceptible and Highly Exposed Populations”
mecdt
of class data.table
, rather than as object nhanes_mec_svy
of class survey.design2
. Also, no longer storing pre-calculated spline fits for serum creatinine and hematocrit vs. age, or pre-calculated age distributions (used by HTTK-Pop in virtual-individuals mode); these are now calculated “on the fly”.race factor
to 1 by default (that is, treat all simulated adults as “non-black” for purposes of GFR estimation), to reflect recent changes in clinical practice. (Control this behavior with httkpop_generate()
argument ckd_epi_race_factor
)httkpop_generate()
argument gfr_resid_var
)default.to.human=TRUE
when rat fup is 0 (Thanks Jim Sluka)get_wetmore...
) for backward compatibility (Thanks Jim Sluka)invitro_mc
to remove inconsistencies and correct handling of fup where median is zero but upper 95th is non-zeroremd0non0u95
to draw random numbers such that the median is zero and the upper 97.5th quantile is non-zero, taking limit of detection into accountcalc_mc_css
and calc_mc_oral_equiv
invitro_mc
to directly allow user to turn uncertainty and variability off (previously this was done by setting CV to NULL)calc_hep_clearance
to the parameterize_X
functions and invitro_mc
– can now be toggled with argument adjusted.Clintcalc_mc_css
were incorrectly calculated in v2.1.0 (only), mg/L units unaffected, but this will have impacted equivalent doses calculated with calc_mc_oralequiv
(Thank you Marc Beal!)calc_half_life
and prohibited the ability to obtain steady state parameters.create_mc_samples
related to default.to.human
argument not being passed to parameterize_schmitt
This version accompanies the submission of the Kapraun et al. manuscript “Evaluation of a Rapid, Generic Human Gestational Dose Model”
solve_fetal_pbtk
and parameterize_fetal_pbtk
load_dawson2021
load_pradeep2020
calc_halflife
(thank you Imran Shah)predict_partitioning_schmitt
removing the hard coded predicted fup regression values from Pearce et al. (2017) and created stand-alone data matrix pearce2017regression read in by the function.convert_units
added to ensure consistency in unit conversions across functionspredict_partitioning_schmitt
– now we read list of tissues needed for a model from modelinfo_X.R
variable alltissuesget_cheminfo
and table chem.phys_and_invitro.data (thank you Lynne Haber and Mark Bradley)add_chemtable
to address ionization (thank you Johann Fribl)get_cheminfo
to incorporate a chemical class filter to remove “PFAS” compounds for all models, except 3compartmentss, based on Wambaugh et al.(2015).calc_ionization
) that caused pKa`s to be ignored in many cases (thank you Wu Yaoxing)get_cheminfo
behavior to change chemical hepatic clearance values where p-value is not consistent with decrease (p-value > clint.pvalue.threshold, default 0.05) to zero.get_cheminfo
behavior to remove fraction unbound in plasma values if credible interval spans from < 0.1 to > 0.9 (turn off with fup.ci.cutoff=FALSE).get_cheminfo
to include median.only argument allowing confidence intervals to be removed for chemical intrinsic hepatic clearance (Clint) values and fraction unbound in plasma (fup) values where they exist (turn on with median.only=TRUE).get_cheminfo
to filter volatile compounds using Henry`s law constant for all models, excluding the gas_pbtk model.calc_stats
to calc_tkstats
– calc_stats
remains temporarily but calls calc_tkstats
calc_stats
and calc_hepatocyte_clearance
get_cheminfo
and parameterize_schmitt
now handle odd cases (like species is zero but human is not) betterget_cheminfo
is now case insensitiveadd_chemtable
(really internal function augment.table
) changed to enforce significant figures (default 4)allow.na
argument to add_chemtable
so that values can be deleted (thanks Nisha Sipes)create_mc_samples
not setting parameter.names variable when parameters are passed to it was fixed by Tom Moxon – thank you!add_chemtable
changed so that pValue and pValue.Reference
set to NA
when Clint is changed (thanks Nisha Sipes)calc_tkstats
corrected to display Rblood2plasmaparameterize_pbtk
get_physchem_param
to look up any missing parameter needed in predicting tissue:plasma partition coefficients using predict_partitioning_schmitt
.set_httk_precision
is now used throughout code to enforce a standard set of significant figures (4) and precision (nothing less than 1e-9).calc_hepatic_clearance
wrapper function for calc_hep_clearance
to allow backwards compatibilityget_chemid
to not crash in certain cases (thank you, Shannon Bell)calc_mc_oral_equivalent
(was sometimes returning all samples unasked, thank you Dan Dawson)This version is consistent with consistent with Linakis et al. (submitted) “Development and Evaluation of a High Throughput Inhalation Model for Organic Chemicals”
calc_analytic_css
calc_mc_css
convert_httkpop
(renamed from convert_httk
)solve_*
model functionshttkpop_biotophys_default
replaces httkpop_bio
convert_httkpop
replaces convert_httk
solve_model
(mostly used by solve_*
model functions)calc_mc_tk
(performs Monte Carlo simulation using a solve_*
function)analytic_css_*
: Model-specific analytic steady-state solutionconvert_httkpop_*
: Model-specific functions for converting HTTK-pop biometrics to model parameterss DSSTox Chemical Structure ID
s (DTXSIDs, see https://comptox.epa.gov/dashboard) now work as chemical identifiers in addition to name and CAS.load_sipes2017
was eliminatedThis version is consistent with the submitted manuscript Wambaugh et al. “Assessing Toxicokinetic Uncertainty and Variability in Risk Prioritization”. Major enhancements were made to allow propagation of measurement-specific uncertainty and population variability into IVIVE predictions.
minimum.Funbound.plasma
argument since some of the Bayesian estimates are very low and at some point the values seem implausible. A value of 0.0001 was selected since it half the lowest reported measured value. Setting minimum.Funbound.plasma=0
removes this restriction.fup.meas.cv=0.4
, clint.meas.cv=0.3
, fup.pop.cv=0.3
, clint.pop.cv=0.3
, (from Wambaugh et al, submitted). Note that most of the new fup measurements have a lower CV than 0.3.calc_analytic_css
to handle all models in the same manner.calc_mc_oral_equivalent
to “mgpkgpday” and “umolpkgpday”. (idea from Katie Paul-Friedman)honda.ivive
argument functionality, reduced to four options as in Honda et al. (2019) Figure 8 panels a-d, changed “plasma.binding” to “bioactive.free.invivo”, and exported function to allow user to call help filehonda.ivive
calc_css
functionscalc_analytic_css
functions, and calc_mc...
functionsget_physchem_param
: exported and now works with vectors of CAS and/or parametersdefault.to.human=TRUE
(human p-value is now used). (thank you Jason Phillips and Shyam Patel for bug report).calc_mc_css
warningscalc_analytic_css
that were causing Css to be over-estimated roughly 10x, therefore reducing the oral equivalent dose 10x (thank you Nisha Sipes for bug report).This version is consistent with the submitted version of Honda et al. “Using the Concordance of In Vitro and In Vivo Data to Evaluate Extrapolation Assumptions”
armitage_eval
armitage_estimate_sarea
calc_mc_css
) to use sets of assumptions identified by Honda et al. (for example, IVIVE=“Honda1”) (thank you Katie Paul-Friedman)load_sipes2017
to be much faster by loading an image by defaultload_sipes2017
.get_wetmore_X
functions changed to get_lit_X
httkpop_bio
exported to user functions (function name since changed to httkpop_biotophys_default
)solve_[MODEL]
functionshematocrit
argument to calc_rblood2plasma
get_cheminfo
help file: exlude.fub.zero
defaults to FALSE
for model 3compartmentss and TRUE
for otherscalc_mc_css
bug: species now passed to function monte_carlo
This version is consistent with the published version of Pearce et al. “Evaluation and calibration of high-throughput predictions of chemical distribution to tissues”. This version contains calibrations for tissue:plasma partition coefficient calibration predictions.
regression
) and adjusted Funbound.plasma (adjusted.Funbound.plasma
).load_sipes2017()
.calc_mc_css
runs faster when not using httkpop and calculating Rblood2plasma, now only calculated once.is.pharma
has been added as a function.calc_analytic_css
does not recalculate all partition coefficients when specifying a tissue.NA
have been replaced with predictions from OPERA where available.parameterize_1comp
) and 3compartmentss (parameterize_steadystate
). Oral doses for these models are now multiplied by hepatic.bioavailability and Fgutabs before entering systemic circulation.modelPBTK.c
, the source file for the pbtk model, now has updated variable names, and corresponding changes are made in solve_pbtk
.calc_mc_css bug
: daily.dose now working as an argument (previously only running as 1).This version is consistent with the JSS publication of Pearce et al. “httk: R Package for High-Throughput Toxicokinetics”.
calc_mc_css
calc_mc_css
, and added faster method for calculating Rblood2plasma for 3compartmentss
.This version includes data and modifications as reported in the recently submitted Pearce et al. paper “Evaluation and Calibration of High-Throughput Predictions of Chemical Distribution to Tissues”.
regression=FALSE
and Funbound.plasma.pc.correction=FALSE
for other models).available_rblood2plasma
parameterize_schmitt
: added force.human.fub
argumentcalc_mc_css
: defaults to direct resampling. no longer coerces species to human when httkpop=TRUE
. When another species is entered, a warning is thrown and the function behaves as if httkpop=FALSE
.Fubound.plasma
when overwrite=FALSE
in add_chemtable
calc_mc_css
: well-stirred correction and new Funbound.plasma
used by default. New partition coefficients used with other models by default.parameterize_3comp
default.to.human
bug – no longer always set to falseThis version is consistent with Ring et al. “Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability”, which is accepted for publication at Environment International. Revisions include models, data, and vignettes for “httk-pop” functionality. “httk-pop” allows Monte Carlo simulation of physiological variability using data from the National Health and Nutrition Examination Survey.
httkpop=FALSE
).default.to.human
argument added to calc_hepatic_clearance
and calc_stats
.calc_hepatic_clearance
and calc_total_clearance
do not necessarily require all parameters.tissue
added to calc_analytic_css
, calc_mc_css
, and calc_mc_oral_equiv
, enabling tissue specific calculations in addition to plasma.calc_dow
argument fraction.neutral
changed to fraction.charged
, thus treating Zwitter ions as neutralssolve_*
functions.get_rblood2plasma
function added to retrieve in vivo Rblood2plasma from chem.physical_and_invitro.data.get_cheminfo
monte_carlo
: Upper bound placed at limit of detection for censored.params
truncated normal distribution. However, this has no impact on the default case where the limit of detection is .01 the mean .005 because of the small standard deviation size (.0015). Only large coefficients of variation or Funbound.plasma values close to the limit of detection would be affected.This revision incorporates changes suggested by the reviewers of Pearce et al., which was accepted, pending minor revision, in the Journal of Statistical Software (now included in vignettes).
This revision adds ~200 more chemicals (from two recent publications including Wetmore et al. (2015) and make several small changes to improve usability and stability.
This version is consistent with a newly submitted article Pearce et al. “httk: R Package for High-Throughput Toxicokinetics” to the Journal of Statistical Software describing use of this package.
Initial public (CRAN) release (March 6, 2015).
These binaries (installable software) and packages are in development.
They may not be fully stable and should be used with caution. We make no claims about them.
Health stats visible at Monitor.