This release accompanies the submission of the new manuscript “Enabling Transparent Toxicokinetic Modeling for Public Health Risk Assessment” and includes changes intended to better faciliate development of new HTTK models through improved model clarity.

In addition we have incorporated comments received on manuscript “Impact of Gut Permeability on Estimation of Oral Bioavailability for Chemicals in Commerce and the Environment” provided by reviewers at ALTEX.

- Cleaned up functions for model 3compartment
- Corrected error where non-restrictive clearance option was not working for model pbtk
- Set restrictive.clearance=TRUE by defailt in ‘calc_hep_clearance’ when model = “unscaled”
- Corrected compartment names for model “gas_pbk” – “Calv”, “Cendexh”, and “Cmixexh” were being returned in ppmv units, while “Calvppmv”, “Cendexhppmv”, and “Cmixexhppmv” were in uM
- Calculation of Fabs corrected for non-human species to follow Yu and Amidon (1999) using small intestine mean residence time and radius. (Thank you ALTEX reviewers)
- Intestinal flow rate correction to the Qgut model now scales with body weight (rodent Fgut was being predicted way too low)
- Corrected units of Peff in calculation of Fabs by ‘calc_fabs.oral’– calculations now indicate that more chemicals are poorly absorbed.
- Revised ‘calc_css’ to handle models with no specified analytic solution
- Revised ionization code in ‘armitage_eval’ so that pka_donor and pka_accept values now correctly used (thank you Meredith Scherer)
- Corrected bug in ‘solve_model’ when only specific times requesed and plots=TRUE (thank you Kimberly Troung)
- Corrected bug with ‘get_chem_id’ when using ‘add_chemtable’ without DTXSIDs (thank you Marc Beal and Miyuki Breen)
- Corrected bug with ‘creater_mc_samples’ where arguments were not getting passed to ‘invitro_mc’ (thank you Hsing-Chieh Lin and Weihsueh Chiu)
- Corrected bug in ‘solve_model’ where tsteps was ignored if times were specified

- A physiology data table from ‘httkpop_generate’ can now be passed to ‘calc_mc_css’ and ‘calc_mc_tk’ (and ‘calc_mc_css’ via …) so that a consistent populatin can be used across monte carlo runs. See argument httkpop.dt.
- Physico-chemical properties are now retrieved from the CompTox Chemicals Dashboard programmatically using R package ctxR (Thank you Paul Kruse)
- ‘calc_fabs.oral’ now calculates oral uptake rate kgutabs using Caco-2 permeability, according to method of Lennernas (1997) (Thank you ALTEX reviewers)
- Revised and changed name of ‘get_fabsgut’ to ‘get_fbio’ and modified function to use ‘calc_fbio.oral’ rather than call oral bioavailability subfunctions directly
- Replaced conversion of human effective gut permeability to rat using Wahajudin et al. (2011) regression (Thank you ALTEX reviewers)
- Loading message displaying version now appears when package is loaded (thank you EPA NAMs class)
- Cleaned up code for various ODE models to make them more consistent and better annotated (added more comments)
- Reordered variables in modelinfo files for consistency so that diff can be used more easily to compare two models
- Modified ‘calc_kair’ to only allow neutral chemical fraction to partition into air (thank you Jon Arnot)
- Updated help files describing models
- Default ODE solver tolerances increased to just below significant figures reported by HTTK (we report 4 sig figs, now require the solver to only converge to 5)
- ‘solve_[MODEL]’ functions now exclusively pass arguments to deSolve through “…”
- New modelinfo file variable default.solver.method can be set – specifies the default ODE solver approach for deSolve if “lsoda” is not desired
- Revised ‘calc_css’ to better calculate the day on which steady-state is reached
- Added internal function ‘check_model’ to provide more informative error messages when key model parameters are missing
- Updated scoping on several functions so that data.tables are handled locally within the functions and not passed by reference.
- Precision of time points added by tsteps argument in ‘solve_model’ now limited to ten times higher than small.time
- Additional time points now reported in ‘solve_model’ immediately after dose events to improve plotting

This patch addresses a number of bugs.

- Argument keepit100 was being improperly ignored by
`get_fabsgut`

- Fixed issue where
`create_mc_samples`

could not handle argumentbeing a list (as in, parameters=parameterize_steadstate(chem.name=“bisphenola”))*parameters* - Error messages for
`calc_css`

now explain that function is only applicable to dynamical (time-evolving) models and handles errors with other models (such as 3compartmentss) more gracefully - Changed Rblood2plasma to Rfblood2plasma for fetal plasma in model fetal_pbtk (Thank you to Kimberly Troung)
- Liquid densities previous referred to as ppmv for
`convert_units`

were actually ppmw. Cannot calculate ppmv without chemical-specific liquid density, which we do not know. - Added model descriptor compartment.state to indicate which compartments are liquid and which are gaseous
- ‘calc_analytic_css_3compss’ was reporting blood concentrations when asked for plasma

- Changed
`armitage_eval`

to allow chemical specification by usual arguments chem.name, chem.cas, and DTXSID. Preserved casrn.vector for backward compatibility. - Changed
`armitage_eval`

to allow multiple instances of chemicals (no longer using CASRN as row names) – thank you Katie Paul Friedman for suggestion - Added Katie Paul Friedman (USEPA) as contributor for long history of suggesting refinements and putting up with bugs
- Function
`solve_model`

now gives warnings when ignoring elements offor a given model and route (acceptible dosing.params are now specified by the modelinfo_[MODEL].R file)*dosing*

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

- Added parameter
to one compartment model so that Monte Carlo works for non-human species*plasma.vol* - Added default units for
and*Aexh*state variables in*Ainh*model so that*gas_pbtk*`calc_css`

works for accumulative chemcials - Corrected the Linakis et al. (2020) vignette to reflect that all CvTdb data used there already are in uM
- Corrected ppbv unit conversions in
`convert_units`

- Precision of time output in
`solve_model`

is no longer restricted to four significant figures - Fixed bug with Monte Carlo functions (for example,
`calc_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) - Revised
`convert_units`

to handle multiple molecular weights – this enables`convert_mc_oral_equivalent`

to take a table of parameters for Monte Carlo - Updated the checks and reported error messages in
`get_clint`

and`get_invtroPK_param`

to be more informative - Corrected calculation of mean blood:plasma partition coefficient when measured RBlood2plasma is avaialble
and*Clint*are now adjusted for*fup**in vitro*binding when`invitrouv=FALSE`

(thanks cm16120)

- Added
*in vitro*measured Caco-2 membrane permeability data for 310 chemicals allowing characterization of oral bioavailability - Added new function
`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) - Added new functions
`calc_fbio.oral`

,`calc_fabs.oral`

, and`calc_fgut.oral`

for calculating systemic bioavailability as \(Fbio = Fabs \times Fgut \times Fhep\) where first-pass hepatic metabolism was already available from`calc_hep_bioavailability`

. - Changed the name of the variable describing fraction absorbed from
the gut prior to first-pass hepatic metabolism to \(Fabsgut\) to reflect that \(Fabs\) and \(Fgut\) are now modeled separately (that is,
).*Fabsgut = Fabs Fgut* - Integrated \(Fabs\) and \(Fgut\) into oral exposure for all TK models
and integrated into population variability and uncertainty functions
within
`invitro_uv`

- Added new function
`benchmark_httk`

to compare current function of the package against historical performance (stored in data.frame`httk.performance`

) - We now skip over the first five minutes when calculating Cmax in
`calc_tkstats`

to allow PBTK model to distribute iv doses

- Added QSPR predictions for Fup and Clint for several thousand
chemicals using the Dawson et al. (2020)
models – accessible from
`load_dawson2021`

(thank you Alex Fisher and Mike Tornero!) - Predicted phys-chem properties for most chemicals using OPERA v2.9 (updated
`armitage_eval`

to properly convert water solubility from OPERA units) - Package now requires
**ggplot2**– will gradually shift all plotting from base R - Returned and updated the Pearce et al. (2017) vignette on Evaluation of Tissue Partitioning
- Revised function
`convert_units`

, expanding the variety of unit conversions available – it is critical to distringuish between state of matter (liquid vs. gas) - Model
allows volatile chemicals again since clearance is amorphous for that model (likely underestimated without exhalation)*1compartment* - Many manuscript references listed in function documentation were converted to a BibTex format from manual insertion of the citations. (thanks Lily Whipple)
- Updated
`get_physchem_param`

to be case-insensitive - New
and*Clint*data curated from literature by ICF from Black et al. (2021), Williamson et al. (2020), Zanelli et al. (2012), Yamagata et al. (2017), and Zanelli et al. (2019) (thank you Noelle Sinski and Colin Guider)*Fup*

- Corrected analytic steady-state functions for PBTK, 3-compartment, and 3-compartment steady-state models to return plasma, not blood concentrations (via blood:plasma ratio)
- Removed inappropriate second adjustment for binding in intrinsic
hepatic clearance assay from
`cal_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) - Fixed major bug in
`calc_ionization`

that caused error when argument pH was a vector – impacts Monte Carlo for ionized compounds - Corrected equation tracking amount inhaled in gas pbtk model (thanks Cecilia Tan)
- Fixed bugs that prevented using Monte Carlo with phys-chem parameters
- Fixed error for species with missing
*in vitro*data (thanks Lu En-Hsuan) - Fixed bug where
`solve_model`

returned other than requested times when argument times was specified (thanks Kimberly Truong)

- Added updated vignette from Pearce et al. (2017): v79i04.R
- Added new vignette on “Introduction to IVIVE”
- Added functions
`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 fup - We now export function
`calc_dow`

for the distribution coefficient - New function
`calc_ma`

separates membrane affinity calculation from`parameterize_schmitt`

- New function
`calc_kair`

separates calculation of blood:air, water:air, and mucus:air partition coefficients from`parameterize_gas_pbtk`

- Added cutoff of logKow/logDow no greater than 6 for
`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 1 - Updated
`calc_analytic_css_pbtk`

to reflect Breen et al. (2022) modification to glomerular filtration in the kidney `get_cheminfo`

now lists required parameters when chemicals are excluded (thanks Ben Savage)- Returned
`daily.dose`

argument to`calc_mc_css`

(still defaults to 1 mg/kg/day) - Simplified arguments needed for
`calc_mc_css`

and`calc_mc_tk`

since now internally using`do.call`

wherever possible to pass arguments - Revised restrictive.clearance argument for function
`solve_model`

- Added inline code comments to
`predict_partitioning_schmitt`

identifying corresponding equations in Schmitt (2008) - Added option
`class.exclude`

to`get_cheminfo`

– defaults to`TRUE`

, but if`FALSE`

then chemical classes are not excluded on the basis of specified model - Updated various function documentation

This 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”

- HTTK-Pop population simulator:
- Replaced HTTK-Pop data from NHANES cycles 2007-2012 with data from
most recent 3 NHANES cycles (2013-2018)

- Reduced size of data file httkpop.RData. NHANES data now stored as
object
`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”. - In CKD-EPI equation used to estimate GFR for simulated adults based
on serum creatinine, age, sex, and race (black/non-black): set
`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`

) - Add residual variability to GFR estimated using CKD-EPI equation, by
default. (Control whether to add residual variability using
`httkpop_generate()`

argument`gfr_resid_var`

)

- Replaced HTTK-Pop data from NHANES cycles 2007-2012 with data from
most recent 3 NHANES cycles (2013-2018)
- Phys-chem properties:
- Replaced
values from Strope et al. (2018) with OPERA (v2.7) predictions (https://github.com/kmansouri/OPERA)*pKa*- This may slightly change all predictions chemicals that are ionized in tissue.

- Replaced
- PBTK model equations:
- Revised renal clearance to be GFR x [Unbound concentration in arterial plasma] (previously it was GFR x [Unbound conc in kidney plasma])

- Miscellaneous:
- Added suggestion message to set
`default.to.human=TRUE`

when ratis 0 (Thanks Jim Sluka)*fup* - Added wrapper functions (
`get_wetmore...`

) for backward compatibility (Thanks Jim Sluka) - Updated
`invitro_mc`

to remove inconsistencies and correct handling ofwhere median is zero but upper 95th is non-zero*fup* - Added internal function
`remd0non0u95`

to draw random numbers such that the median is zero and the upper 97.5th quantile is non-zero, taking limit of detection into account - Revised and expanded documentation for
`calc_mc_css`

and`calc_mc_oral_equiv`

- Added suggestion message to set
- Added logical arguments to
`invitro_mc`

to directly allow user to turn uncertainty and variability off (previously this was done by setting CV to NULL) - If Monte Carlo for the
measurement (that is, uncertainty) is turned off user may choose to provide columns for*fup*or*unadjusted.Funbound.plasma*

from their own methods*fup.mean* - Moved Kilford et
al. (2008) correction for fraction unbound in hepatocyte assay from
`calc_hep_clearance`

to the`parameterize_X`

functions and`invitro_mc`

– can now be toggled with argument*adjusted.Clint* - New vignette “Introduction to HTTK” added that includes material from Breen et al. (2021)

- uM units on
`calc_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!) - User provided DTXSID chemical identifiers were not passed
appropriately in the
`calc_half_life`

and prohibited the ability to obtain steady state parameters. - Error fixed in
`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”

- New HT-PBTK model added as described by Kapraun et
al. (submitted) including functions
`solve_fetal_pbtk`

and`parameterize_fetal_pbtk`

- QSAR predicted chemical-specific plasma protein unbound plasma
fraction (
) and intrinsic hepatic clearance (*fup*) values data from Dawson et al. (2021) is now included as Dawson2021 and can be added with the new function:*Clint*`load_dawson2021`

- QSAR predicted chemical-specific plasma protein unbound plasma
fraction (
) and intrinsic hepatic clearance values (*fup*) data from Pradeep et al. (2020) is now included as Pradeep2020 and can be added with the new function:*Clint*`load_pradeep2020`

- Added function
`calc_halflife`

(thank you Imran Shah)

- Updated
`predict_partitioning_schmitt`

removing the hard coded predictedregression values from Pearce et al. (2017) and created stand-alone data matrix*fup*read in by the function.*pearce2017regression* - Internal reusable function
`convert_units`

added to ensure consistency in unit conversions across functions - Units corrected for gas_pbtk model to more naturally handle ppmv (parts per million by volume) and uM
- Reworked code for
`predict_partitioning_schmitt`

– now we read list of tissues needed for a model from`modelinfo_X.R`

variable*alltissues* - Further revised documentation to Armitage et al. (2014) functions (thank you Madison Feshuk)
- Expanded documentation for function
`get_cheminfo`

and table(thank you Lynne Haber and Mark Bradley)*chem.phys_and_invitro.data*

- Expanded example for
`add_chemtable`

to address ionization (thank you Johann Fribl) - Added
data from Dawson (2021) training set (CHEMBL)*Clint* - Revised
`get_cheminfo`

to incorporate a chemical class filter to remove “PFAS” compounds for all models, except, based on Wambaugh et al.(2015).*3compartmentss*

- Corrected swapped
values in table*area_bottom*for the Armitage model. (thank you Todor Antonijevic)*well_param* - Contribution from Todor Antonijevic:
,*this.conc_ser_alb*, and*this.conc_ser_lip*added to the list of arguments.*this.Vdom*- the volume of headspace calculated as in Armitage et al. (2014).
- the volume of medium calculated as in Armitage et al. (2014).
calculated as in Armitage et al. (2014)*f_ratio*added in the denominator of*kow*, that is*cwat***kowP_domf_oc*Vdom- Corrected major bug introduced in 2.0.0 (vectorization of
`calc_ionization`

) that causedto be ignored in many cases (thank you Wu Yaoxing)*pKa`s* - Corrected monkey cardiac output (thank you Peter Egeghy)
- Corrected rabbit plasma volume and total body water (thank you Jo Nyffeler)

- Sarah Davidson is new lead HTTK software engineer (thank you Mark Sfeir!)
- Added Xiaoqing Chang and Shannon Bell as contributors thanks to substantial efforts improving the package
- Changed DESCRIPTION to indicate LazyDataCompression is xz
- Revised and expanded documentation for functions related to Armitage et al. 2014
*in vitro*distribution model – armitage_eval() and armitage_estimate_sarea() - Revised documentation to several functions missing value description (thank you Julia Haider and Gregor Seyer)
- Revised examples where arguments had changed (thank you Julia Haider)
- Revised and expanded documentation for functions related to Armitage et al. 2014
*in vitro*distribution model – armitage_eval() and armitage_estimate_sarea() - Revised
`get_cheminfo`

behavior to change chemical hepatic clearance values where p-value is not consistent with decrease (p-value >, default 0.05) to zero.*clint.pvalue.threshold* - Revised
`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* - Revised
`get_cheminfo`

to includeargument allowing confidence intervals to be removed for chemical intrinsic hepatic clearance (*median.only*) values and fraction unbound in plasma (*Clint*) values where they exist (turn on with median.only=TRUE).*fup* - Revised
`get_cheminfo`

to filter volatile compounds using Henry`s law constant for all models, excluding themodel.*gas_pbtk*

- Fixed problems with
values reported from Wood et al. 2017, fraction unbound in hepatocyte assay adjustment was being applied twice (thank you Xiaoqing Chang)*Clint* - Fixed problems with clearance from source “Ito/Riley”: “not determined” was mistakenly being interpreted as “0” rather than not measured (thank you Xiaoqing Chang)

- Updated literature chemical-specific human and rat
*in vitro*data:- Revised human and rat VOC chemical numbers to match Linakis et al. (2020)
- Replaced “Obach” human pharmaceutical data from Obach et al. (2008) with data from Lombardo et al. (2018)
- Added new human data from EU JRC (Paini et al., 2020)
- Steady-state model
) now works for 1016 chemicals in human and 212 in rat*3compartmentss*

- Renamed
`calc_stats`

to`calc_tkstats`

–`calc_stats`

remains temporarily but calls`calc_tkstats`

- Added warnings to deprecated function names
`calc_stats`

and`calc_hepatocyte_clearance`

- Revised how default.to.human works, so that
`get_cheminfo`

and`parameterize_schmitt`

now handle odd cases (like species is zero but human is not) better - Argument
for*info*`get_cheminfo`

is now case insensitive `add_chemtable`

(really internal function`augment.table`

) changed to enforce significant figures (default 4)- OPERA phys-chem properites provided by CompTox Chemicals Dashboard have been slightly revised
- Updated documentation to well parameters for Armitage et al. (2014) model (thank you Katie Paul-Friedman and Greg Honda)
- added
`allow.na`

argument to`add_chemtable`

so that values can be deleted (thanks Nisha Sipes)

- Fixed logic statement in solve_model to eliminate warning
- Problem with
`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`

whenis changed (thanks Nisha Sipes)*Clint*- Output for
`calc_tkstats`

corrected to display*Rblood2plasma* - Minor fix with argument
in*suppress.messages*`parameterize_pbtk`

- Updated default dosing scheme so that a single-time, initial
comes into effect if no other dosing information is specified, and any dosing info that is specified using whatever dosing arguments overrides the default. Combinations of dosing arguments can still be specified.*dose* - Adjusted
model to effectively make use of any passed chemical identifier information, especially as it is needed in using*3compartmentss*`get_physchem_param`

to look up any missing parameter needed in predicting tissue:plasma partition coefficients using`predict_partitioning_schmitt`

.

- Fixed errors in the different models` steady state solver functions to support parameter input of key object types, especially lists and compound data.tables/data.frames. (thank you, Nisha Sipes)

- New function
`set_httk_precision`

is now used throughout code to enforce a standard set of significant figures (4) and precision (nothing less than 1e-9).

- Added
`calc_hepatic_clearance`

wrapper function for`calc_hep_clearance`

to allow backwards compatibility - Revised
`get_chemid`

to not crash in certain cases (thank you, Shannon Bell) - Revised Linakis et al. (submitted) vignette

- Fixed output of
`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”

- New generic inhalation PBPK model
*gas_pbtk* - New chemical specific parameters for volatile chemicals have been
added:
- 43 in human
- 41 in rat

- Significantly rewrote underlying code to allow more easy integration
of new models. (goodbye spaghetti code!)
- Rewritten functions include:
`calc_analytic_css`

`calc_mc_css`

`convert_httkpop`

(renamed from`convert_httk`

)`solve_*`

model functions

- Renamed a few httk-pop functions for clarity:
`httkpop_biotophys_default`

replaces`httkpop_bio`

`convert_httkpop`

replaces`convert_httk`

- New functions introduced:
`solve_model`

(mostly used by`solve_*`

model functions)`calc_mc_tk`

(performs Monte Carlo simulation using a`solve_*`

function)

- Models must be much more thoroughly described now, with all relevant information placed in modelinfo_* files in the /R directory.
- New model-specific functions introduced:
`analytic_css_*`

: Model-specific analytic steady-state solution`convert_httkpop_*`

: Model-specific functions for converting HTTK-pop biometrics to model parameters

- Beta testing and bug reports provided by Xiaoqing Chang.

- Rewritten functions include:
- EPA
`s DSSTox Chemical Structure ID`

s (DTXSIDs, see https://comptox.epa.gov/dashboard) now work as chemical identifiers in addition to name and CAS. - Results now truncated to appropriate significant figures (4) and precision (1e-12).
- New physiological parameters have been added for monkeys
- To decrease package size the
option of*load image*`load_sipes2017`

was eliminated - Added vignette for Figure 6 from Frank, et al. (2018) “Defining toxicological tipping points in neuronal network development.”

- Changed all file name starting letters to lowercase.

- Many bug fixes (thank you David Trudel).

This 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.

- New human experimental measurements of
and*fup*are reported for 418 and 467 chemicals, respectively.*Clint*- Data on both
and*fup*are jointly available for 389 of those chemicals.*Clint*

- Data on both
and*Clint*values can now be either numeric values (as before) or distributions characterized by as “MEDIAN,LOWER95TH,UPPER95TH,PVALUE” for*fup*and “MEDIAN,LOWER95TH,UPPER95TH” for*Clint*. The code has been substantially revised to accommodate this.*fup*

- Added a
`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. - Monte Carlo coefficient of variation for
and*Clint*has been divided into separate values for uncertainty (from measurement) and variability (population/genetic). Default values for coefficients of variation are*fup*`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 newmeasurements have a lower CV than 0.3.*fup* - All documentation converted to
**roxygen2**format. - Vignette names have been updated to make the related publication clear
- All references to
(previously “fraction unbound” but confusing with “fraction unbound in blood”) have been converted to*fub*(the intended “fraction unbpund in plasma”) where appropriate.*fup* - Rewrote
`calc_analytic_css`

to handle all models in the same manner. - Changed argument values “mg” and “mol” for
in*output.units*`calc_mc_oral_equivalent`

to “mgpkgpday” and “umolpkgpday”. (idea from Katie Paul-Friedman) - Changed httk-pop argument
to*fup.censor*.*fup.censored.dist* - Armitage et
al. (2014) model functions now work with input of vectors (to allow
*data.table*compatibility) or input of*data.table* - Added the physico-chemical parameters needed to run Armitage et al. model
- Updated
`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 file - Added
as an option set by*concentration*`honda.ivive`

- Added
as an option to*concentration = “tissue”*`calc_css`

functions - Added
as an option to*bioactive.free.invivo*`calc_analytic_css`

functions, and`calc_mc...`

functions - Function
`get_physchem_param`

: exported and now works with vectors of CAS and/or parameters

- Corrected error where non-human species were using the incorrect
p-value for
when*Clint*`default.to.human=TRUE`

(human p-value is now used). (thank you Jason Phillips and Shyam Patel for bug report). - Shyam Patel (Sciome) identified an error in how flow means were scaled by age in httk-pop Monte Carlo sampler.
- Fixed
`calc_mc_css`

warnings

- Updated tests to reflect correct model predictions.
- Fixed errors that was causing the
and*3compartmentss*models to not work with Monte Carlo. (thank you Jo Nyffeler for bug report).*1compartment*

- Fixed significant errors in
`calc_analytic_css`

that were causingto be over-estimated roughly 10x, therefore reducing the oral equivalent dose 10x (thank you Nisha Sipes for bug report).*Css*

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”

- New rat-specific
*in vitro*TK data provided for 65 chemicals (Honda et al.) - New functions for calculating
*in vitro*disposition according to the Armitage et al. (2014) model (thank you James Armitage):`armitage_eval`

`armitage_estimate_sarea`

- Mark Sfeir is new lead HTTK software engineer (thank you Robert Pearce!)
- Moved code base to Bitbucket internally (thank you Sean Watford and Jeremy Dunne)
- Added arguments to IVIVE functions (for example,
`calc_mc_css`

) to use sets of assumptions identified by Honda et al. (for example, IVIVE=“Honda1”) (thank you Katie Paul-Friedman) - Changed all model parameter sets to include physico-chemical properties to better facilitate Monte Carlo analysis
- Updated
`load_sipes2017`

to be much faster by loading an image by default - Updated help files for Sipes2017 and
`load_sipes2017`

. `get_wetmore_X`

functions changed to`get_lit_X`

`httkpop_bio`

exported to user functions (function name since changed to`httkpop_biotophys_default`

)- For time point after first dose: bug now corrected when not starting at time 0 (thank you Xiaoqing Chang)
- Added figures to help files of
`solve_[MODEL]`

functions - Added
`hematocrit`

argument to`calc_rblood2plasma`

- Changed amounts in model
to not bescaled by body weight, added*1compartment*to parameters for that model thank you Tom Moxon)*BW* - Converted all phys-chem properties except
to values predicted by OPERA (Mansouri et al., 2018) – see https://github.com/NIEHS/OPERA*pKa* - Added missing
and*logP*for some chemicals using predictions from OPERA*MW* - Renamed and added vignettes

- Corrected mistake in
`get_cheminfo`

help file:`exlude.fub.zero`

defaults to`FALSE`

for modeland*3compartmentss*`TRUE`

for others - Corrected (thank you Jason Phillips), updated, and added
values from Strope et al. (2018)*pKa* - Corrected
`calc_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.

- Added arguments to multiple functions for whether or not to use new
calibration regressions (
`regression`

) and adjusted(*Funbound.plasma*`adjusted.Funbound.plasma`

). - Hepatic clearance and plasma binding predictions for ~8000 chemicals
from Simulations Plus ADMET Predictor used in Sipes et al. (2017)
is now included as
and can be added with the new function:*Sipes2017*`load_sipes2017()`

. - New data has been added from an IVIVE evaluation of toxicokinetics
Wambaugh et al. 2018
- New toxicokinetic concentration vs. time data were added to
(full time course) and*chem.invivo.PK.data*(TK statistics such as Cmax and AUC on a per treatment basis).*chem.invivo.PK.summary.data* - A new table is included:
(TK statistics such as volume of distribution and elimination rate on a per chemical basis)*chem.invivo.PK.aggregate data* default changed to 2.18.*kgutabs*

- New toxicokinetic concentration vs. time data were added to

values from Wetmore et al. 2012 and 2013 that were previously rounded to 2 decimal places are now rounded to 3, resulting in additional compounds with measurable*Funbound.plasma*that were otherwise assumed to be below the limit of detection.*Funbound.plasma*data is now readable when values are separated by a semicolon rather than a comma. These values were previously misread as neutral.*pKa*- Partition coefficients can now be predicted without calculating all of them, using the tissues argument.
`calc_mc_css`

runs faster when not using httkpop and calculating, now only calculated once.*Rblood2plasma*is updated, and*chem.lists*`is.pharma`

has been added as a function.`calc_analytic_css`

does not recalculate all partition coefficients when specifying a tissue.values from EPISuite or valued*logP*`NA`

have been replaced with predictions from OPERA where available.- First-pass hepatic metabolism has been added in the form of the
parameter
to the models*hepatic.bioavailability*(*1compartment*`parameterize_1comp`

) and(*3compartmentss*`parameterize_steadystate`

). Oral doses for these models are now multiplied byand*hepatic.bioavailability*before entering systemic circulation.*Fgutabs* and*kinhabs*, both of which were unused in the models, are removed.*kdermabs*`modelPBTK.c`

, the source file for themodel, now has updated variable names, and corresponding changes are made in*pbtk*`solve_pbtk`

.- The time step immediately after addition of dose is added to better capture peak concentration for iv dosing.

- Corrected
`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”.

- Corrected intrinsic clearances for (about 10) compounds from Brown et al. (2007),
- Corrected output message from
`calc_mc_css`

- Corrected
used for predicting partitioning into interstitial protein (negligible difference in predictions)*Funbound.plasma* - Corrected bug in calculating
in*Rblood2plasma*`calc_mc_css`

, and added faster method for calculatingfor*Rblood2plasma*`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”.

- The Schmitt (2008) method for partition coefficients has been modified and calibrated using experimental data.
- The new method is now default, although the previous approach is
available (set
`regression=FALSE`

and`Funbound.plasma.pc.correction=FALSE`

for other models).

- The membrane affinity regression has been updated and always used in place of the old approach
- Added function
`available_rblood2plasma`

*in vivo*used when available*Rblood2plasma*- well-stirred blood correction and restrictive.clearance options added
- New
*in vitro*data from Uchimura et al. (2010), Brown et al. (2007) and Pirovano et al. (2016), Gulden et al. (2002) - Tonnelier et
al. (2012)
values of 0.005 changed to 0 in*Funbound.plasma**chem.physical_and_invitro.data* - New
with Ruark et al. (2014) that contains different formatting with human and rat specific data*tissue.data table* `parameterize_schmitt`

: added`force.human.fub`

argument- added plasma protein and neutral lipid volume fractions to
for use in package*physiology.data* `calc_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`

.- updated help file references and examples
- removed temperature from Schmitt parameters
- overwrite 0 values for
`Fubound.plasma`

when`overwrite=FALSE`

in`add_chemtable`

- added vignette for generating partition coefficient plots
- added DSSTOX info, new columns:
,*DSSTox_Substance_Id*, or*Structure_Formula*. overwrote:*Substance_Type*and*MW**SMILES* - added
and*pc.data*tables*obach2008* - httkpop option in
`calc_mc_css`

: well-stirred correction and new`Funbound.plasma`

used by default. New partition coefficients used with other models by default.

- corrected
`parameterize_3comp`

`default.to.human`

bug – no longer always set to false

This 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.

- httk-pop Monte Carlo human variability functionality is the new
default, although the previous approach is available (set
`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.- Argument
`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 neutrals- Multiple iv doses enabled in
`solve_*`

functions. `get_rblood2plasma`

function added to retrieve*in vivo*from*Rblood2plasma*.*chem.physical_and_invitro.data*

- Corrected minor bug for
`get_cheminfo`

- Corrected bug in
`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 orvalues close to the limit of detection would be affected.*Funbound.plasma*

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).

- Table name
changed to*PK.physiology.data*.*physiology.data*

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.

- This revision changes some model parameter names to follow a more systematic naming convention.
- Minor bugs have been corrected.

Initial public (CRAN) release (March 6, 2015).