# Linakis et al. (2020): Analysis and Figure Generation

#### Matt Linakis

#### January 30, 2020

mlinak01@gmail.com

## Abstract

Currently it is difficult to prospectively estimate human toxicokinetics (particularly for novel chemicals) in a high-throughput manner. The R software package httk has been developed, in part, to address this deficiency, and the aim of this investigation was to develop a generalized inhalation model for httk. The structure of the inhalation model was developed from two previously published physiologically-based models from Jongeneelen et al. (2011) and Clewell et al. (2001) while calculated physicochemical data was obtained from EPA’s CompTox Chemicals Dashboard. In total, 142 exposure scenarios across 41 volatile organic chemicals were modeled and compared to published data. The slope of the regression line of best fit between log-transformed simulated and observed combined measured plasma and blood concentrations was 0.59 with an r2= 0.54 and a Root Mean Square Error (RMSE) of direct comparison between the log-transformed simulated and observed values of 0.87. Approximately 3.6% (n = 73) of the data points analyzed were > 2 orders of magnitude different than expected. The volatile organic chemicals examined in this investigation represent small, generally lipophilic molecules. Ultimately this paper details a generalized inhalation component that integrates with the httk physiologically-based toxicokinetic model to provide high-throughput estimates of inhalation chemical exposures.

## Prepare for session

### Load the relevant libraries

    knitr::opts_chunk$set(echo = TRUE, fig.width=5, fig.height=4)
    library(httk)
    library(ggplot2)
    library(gridExtra)

    ##
    ## Attaching package: 'gridExtra'

    ## The following object is masked from 'package:gdata':
    ##
    ##     combine

    library(cowplot)
    library(ggrepel)
    library(dplyr)

    ##
    ## Attaching package: 'dplyr'

    ## The following object is masked from 'package:gridExtra':
    ##
    ##     combine

    ## The following objects are masked from 'package:data.table':
    ##
    ##     between, first, last

    ## The following objects are masked from 'package:gdata':
    ##
    ##     combine, first, last

    ## The following objects are masked from 'package:stats':
    ##
    ##     filter, lag

    ## The following objects are masked from 'package:base':
    ##
    ##     intersect, setdiff, setequal, union

    library(stringr)
    library(forcats)
    library(smatr)
    # Delete all objects from memory:
    rm(list=ls())
    # We love to give warning messages whenever assumptions are used by HTTK,
    # but they will overwhelm the output of this vignette so we turn them
    # off:
    options(warn = -1)

###Get metabolism and concentration data

    met_data <- metabolism_data_Linakis2020
    conc_data <- concentration_data_Linakis2020

## ANALYSIS

Identify chemicals currently in our metabolism data that we don’t have good concentration/time data for and remove them from our training dataset

### Data summary for chemical properties

    # Small molecule chemicals
    summary(met_data$AVERAGE_MASS)

    ##    Min. 1st Qu.  Median    Mean 3rd Qu.    Max.
    ##   32.04   84.93  102.18  110.28  131.38  252.32

    # Generally more lipophilic chemicals
    summary(met_data$OCTANOL_WATER_PARTITION_LOGP_OPERA_PRED)

    ##    Min. 1st Qu.  Median    Mean 3rd Qu.    Max.
    ## -0.6059  1.0047  1.9649  2.1152  2.8737  6.1309

    # Unsurprisingly then, the chemicals are generally less water-soluble
    summary(met_data$WATER_SOLUBILITY_MOL.L_OPERA_PRED)

    ##      Min.   1st Qu.    Median      Mean   3rd Qu.      Max.
    ##  0.000000  0.001759  0.013948  2.073901  0.254380 26.122900

    # ~60% of samples in humans
    table(conc_data$CONC_SPECIES)/nrow(conc_data)*100

    ##
    ##    Human      Rat
    ## 59.80392 40.19608

    # ~72% of samples are from blood
    table(conc_data$SAMPLING_MATRIX)/nrow(conc_data)*100

    ##
    ##        ABL         BL    BL (+W)         EB    EB (+W)        EEB        MEB
    ##  4.2483660 35.3408030  0.6069094 24.8366013  0.7002801  2.1008403  0.4668534
    ##         PL        VBL
    ##  1.4472456 30.2521008

### Exposure scenarios

    # Create a dataframe with 1 row for each unique external exposure scenario
    unique_scenarios <- conc_data[with(conc_data,
      order(PREFERRED_NAME,
            CONC_SPECIES,
            SAMPLING_MATRIX,
            as.numeric(as.character(DOSE)),EXP_LENGTH,-TIME)),] %>%
      distinct(DTXSID,DOSE,DOSE_U,EXP_LENGTH,CONC_SPECIES,SAMPLING_MATRIX, .keep_all = TRUE)

### Observations and Predictions

Create a list of dataframes of observed and predicted concentrations for each unique external exposure scenario

    plist <- list()
    simlist <- list()
    obslist <- list()
    for(i in 1:nrow(unique_scenarios)){
      #tryCatch({
        relconc <- subset(conc_data,conc_data$DTXSID == unique_scenarios$DTXSID[i] &
          conc_data$DOSE == unique_scenarios$DOSE[i] &
          conc_data$EXP_LENGTH == unique_scenarios$EXP_LENGTH[i] &
          conc_data$CONC_SPECIES == unique_scenarios$CONC_SPECIES[i] &
          conc_data$SAMPLING_MATRIX == unique_scenarios$SAMPLING_MATRIX[i])
        obslist[[i]] <- relconc
        name <- paste0("out",i)
        if(as.character(unique_scenarios$CONC_SPECIES[i]) == "Human"){
          solve <- assign(name, solve_gas_pbtk(
            chem.cas = unique_scenarios$CASRN[i],
            days = (unique_scenarios$TIME[i]+unique_scenarios$EXP_LENGTH[i]),
    # Make sure we get conc's at the observed times:
            times=signif(obslist[[i]]$TIME,4),
            tsteps = 500,
            exp.conc = ((as.numeric(unique_scenarios$DOSE[i])*1e20*1000)/24450)/1e20,
            exp.duration = unique_scenarios$EXP_LENGTH[i]*24,
            period = (unique_scenarios$TIME[i]+unique_scenarios$EXP_LENGTH[i])*24,
            species = as.character(unique_scenarios$CONC_SPECIES[i]),
            vmax.km = F,
            vmax = met_data$VMAX[met_data$CASRN %in% unique_scenarios$CASRN[i] &
            met_data$SPECIES == unique_scenarios$CONC_SPECIES[i]],
            km = met_data$KM[met_data$CASRN %in% unique_scenarios$CASRN[i] &
            met_data$SPECIES == unique_scenarios$CONC_SPECIES[i]],
            suppress.messages=T))
        } else {
          solve <- assign(name, solve_gas_pbtk(
            chem.cas = unique_scenarios$CASRN[i],
            days = (unique_scenarios$TIME[i]+unique_scenarios$EXP_LENGTH[i]),
    # Make sure we get conc's at the observed times:
            times=signif(obslist[[i]]$TIME,4),
            tsteps = 500,
            exp.conc = ((as.numeric(unique_scenarios$DOSE[i])*1e20*1000)/24450)/1e20,
            exp.duration = unique_scenarios$EXP_LENGTH[i]*24,
            period = (unique_scenarios$TIME[i]+unique_scenarios$EXP_LENGTH[i])*24,
            species = as.character(unique_scenarios$CONC_SPECIES[i]),
            vmax.km = T,
            vmax = met_data$VMAX[met_data$CASRN %in% unique_scenarios$CASRN[i] &
            met_data$SPECIES == unique_scenarios$CONC_SPECIES[i]],
            km = met_data$KM[met_data$CASRN %in% unique_scenarios$CASRN[i] &
            met_data$SPECIES == unique_scenarios$CONC_SPECIES[i]],
            suppress.messages=T))
        }
        #browser()
        solve <- as.data.frame(solve)
        # Sets the output units appropriate for the sampling matrix
        if (unique_scenarios$SAMPLING_MATRIX[i] == "VBL" |
          unique_scenarios$SAMPLING_MATRIX[i] == "BL" |
          unique_scenarios$SAMPLING_MATRIX[i] == "BL (+W)")
        {
          solve$simconc <- solve$Cven
          solve$unit <- "uM"
        } else if (unique_scenarios$SAMPLING_MATRIX[i] == "ABL") {
          solve$simconc <- solve$Cart
          solve$unit <- "uM"
        } else if (unique_scenarios$SAMPLING_MATRIX[i] == "EB" |
          unique_scenarios$SAMPLING_MATRIX[i] == "EEB" |
          unique_scenarios$SAMPLING_MATRIX[i] == "EB (+W)")
        {
          solve$simconc <- solve$Cendexh * 24.45
          solve$unit <- "ppm"
        } else if (unique_scenarios$SAMPLING_MATRIX[i] == "MEB") {
          solve$simconc <- solve$Cmixexh * 24.45
          solve$unit <- "ppm"
        } else if (unique_scenarios$SAMPLING_MATRIX[i] == "PL"){
          solve$simconc <- solve$Cplasma
          solve$unit <- "uM"
        } else {
          solve$simconc <- NA
          solve$unit <- NA
        }
        simlist[[i]] <- solve
        plot.data <- solve
        name1 <- paste0("c.vs.t",i)
    #Right now this is only calculating real concentrations according to mg/L in blood
        plots <- assign(name1, ggplot(plot.data, aes(time*24, simconc)) +
          geom_line() +
          xlab("Time (h)") +
          ylab(paste0("Simulated ",
            unique_scenarios$SAMPLING_MATRIX[i],
            "\nConcentration (" ,
            solve$unit, ")")) +
          ggtitle(paste0(
            unique_scenarios$PREFERRED_NAME[i],
            " (",
            unique_scenarios$CONC_SPECIES[i],
            ", ",
            round(as.numeric(unique_scenarios$DOSE[i]), digits = 2),
            unique_scenarios$DOSE_U[i],
            " for ",
            round(unique_scenarios$EXP_LENGTH[i]*24, digits = 2),
            "h in ",
            unique_scenarios$SAMPLING_MATRIX[i], ")")) +
          geom_point(data = relconc, aes(TIME*24,CONCENTRATION)) +
          theme(text = element_text(size=10))+
          theme_bw())
        plist[[i]] <- plots
      #}, error = function(e){})
    }
    rm(list=ls(pattern='out'))
    rm(list=ls(pattern='c.vs.t'))

Create a list to hold the combined observations and predictions for each scenario:

    # Creation of simulated vs. observed concentration dataset
    unique_scenarios$RSQD <- 0
    unique_scenarios$RMSE <- 0
    unique_scenarios$AIC <- 0
    simobslist <- list()
    obvpredlist <- list()

Merge the simulations and observations on the basis of simualation time:

    for(i in 1:length(simlist))
    {
      obsdata <- as.data.frame(obslist[[i]])
      simdata <- as.data.frame(simlist[[i]])
    # skips over anything for which there was no observed data or
    # insufficient information to run simulation:
      if (!is.null(simlist[[i]]) & !is.null(obslist[[i]]))
      {
    # Make sure we are looking at consistent time points:
        simobscomb <- simdata[simdata$time %in% signif(obsdata$TIME,4),]
        obsdata <- subset(obsdata,signif(TIME,4) %in% simobscomb$time)
    # Merge with obsdata
        colnames(obsdata)[colnames(obsdata) ==
          "TIME"] <-
          "obstime"
    # Round to match sim time:
        obsdata$time <- signif(obsdata$obstime,4)
        colnames(obsdata)[colnames(obsdata) ==
          "CONCENTRATION"] <-
          "obsconc"
        colnames(obsdata)[colnames(obsdata) ==
          "PREFERRED_NAME"] <-
          "chem"
        colnames(obsdata)[colnames(obsdata) ==
          "DOSE"] <-
          "dose"
        colnames(obsdata)[colnames(obsdata) ==
          "EXP_LENGTH"] <-
          "explen"
        colnames(obsdata)[colnames(obsdata) ==
          "CONC_SPECIES"] <-
          "species"
        colnames(obsdata)[colnames(obsdata) ==
          "SAMPLING_MATRIX"] <-
          "matrix"
        colnames(obsdata)[colnames(obsdata) ==
          "AVERAGE_MASS"] <-
          "mw"
        colnames(obsdata)[colnames(obsdata) ==
          "ORIG_CONC_U"] <-
          "orig_conc_u"
        simobscomb <- suppressWarnings(merge(obsdata[,c(
          "time",
          "obstime",
          "obsconc",
          "chem",
          "dose",
          "explen",
          "species",
          "matrix",
          "mw",
          "orig_conc_u"
          )], simobscomb, by="time", all.x=T))

    # Merge with met_data
        this.met_data <- subset(met_data,
          PREFERRED_NAME == simobscomb[1,"chem"] &
          SPECIES == simobscomb[1,"species"])
        colnames(this.met_data)[colnames(this.met_data)=="CHEM_CLASS"] <-
          "chemclass"
        colnames(this.met_data)[colnames(this.met_data) ==
          "OCTANOL_WATER_PARTITION_LOGP_OPERA_PRED"] <-
          "logp"
        colnames(this.met_data)[colnames(this.met_data) ==
          "WATER_SOLUBILITY_MOL.L_OPERA_PRED"] <-
          "sol"
        colnames(this.met_data)[colnames(this.met_data) ==
          "HENRYS_LAW_ATM.M3.MOLE_OPERA_PRED"] <-
          "henry"
        colnames(this.met_data)[colnames(this.met_data) ==
          "VMAX"] <-
          "vmax"
        colnames(this.met_data)[colnames(this.met_data) ==
          "KM"] <-
          "km"
        simobscomb <- suppressWarnings(cbind(simobscomb,this.met_data[c(
          "chemclass",
          "logp",
          "sol",
          "henry",
          "vmax",
          "km")]))
        simobslist[[i]] <- simobscomb
      }
    }

Identify the appropriate matric (for example, exhaled breath) for each observation:

    for(i in 1:length(simobslist))
      if (nrow(simobslist[[i]])>0)
      {
        simobscomb <- simobslist[[i]]
      # Match the matrix for each observation:
        for (j in 1:nrow(simobscomb))
          if(!is.na(simobscomb$matrix[j]))
          {
            if (simobscomb$matrix[j] == "VBL" |
                simobscomb$matrix[j] == "BL" |
                simobscomb$matrix[j] == "BL (+W)")
            {
              simobscomb$simconc[j] <- simobscomb$Cven[j]
            } else if (simobscomb$matrix[j] == "ABL") {
              simobscomb$simconc[j] <- simobscomb$Cart[j]
            } else if (simobscomb$matrix[j] == "EB" |
                       simobscomb$matrix[j] == "EEB" |
                       simobscomb$matrix[j] == "EB (+W)") {
              simobscomb$simconc[j] <- simobscomb$Cendexh[j] * 24.45
            } else if (simobscomb$matrix[j] == "MEB") {
              simobscomb$simconc[j] <- simobscomb$Cendexh[j] * 24.45
            } else if (simobscomb$matrix[j] == "PL") {
              simobscomb$simconc[j] <- simobscomb$Cplasma[j]
            } else {
              simobscomb$simconc[j] <- NA
            }
          }
        simobslist[[i]] <- simobscomb
      }

Identify which quartile each observation occured in with respect to the latest (maximum) observed time

    for(i in 1:length(simobslist))
      if (nrow(simobslist[[i]])>0)
      {
        simobscomb <- simobslist[[i]]
        for (j in 1:nrow(simobscomb))
        {
          max.time <- max(simobscomb$time,na.rm=T)
          if (is.na(max.time)) simobscomb$tquart <- NA
          else if (max.time == 0) simobscomb$tquart <- "1"
          else if (!is.na(simobscomb$time[j]))
          {
            simobscomb$tquart[j] <- as.character(1 +
              floor(simobscomb$time[j]/max.time/0.25))
            simobscomb$tquart[simobscomb$tquart=="5"] <-
              "4"
          } else simobscomb$tquart[j] >- NA
        }
        simobslist[[i]] <- simobscomb
      }

Calculate the area under the curve (AUC)

    for(i in 1:length(simobslist))
      if (nrow(simobslist[[i]])>0)
      {
        simobscomb <- simobslist[[i]]
    # Calculat the AUC with the trapezoidal rule:
        if (nrow(simobscomb)>1)
        {
          for (k in 2:max(nrow(simobscomb)-1,2,na.rm=T))
          {
            simobscomb$obsAUCtrap[1] <- 0
            simobscomb$simAUCtrap[1] <- 0
            if (min(simobscomb$time) <= (simobscomb$explen[1]*1.03) &
                nrow(simobscomb) >=2)
            {
              simobscomb$obsAUCtrap[k] <- simobscomb$obsAUCtrap[k-1] +
                0.5*(simobscomb$time[k] - simobscomb$time[k-1]) *
                (simobscomb$obsconc[k] + simobscomb$obsconc[k-1])
              simobscomb$simAUCtrap[k] <- simobscomb$simAUCtrap[k-1] +
                0.5*(simobscomb$time[k]-simobscomb$time[k-1]) *
                (simobscomb$simconc[k] + simobscomb$simconc[k-1])
            } else {
              simobscomb$obsAUCtrap <- 0
              simobscomb$simAUCtrap <- 0
            }
          }
        } else {
          simobscomb$obsAUCtrap <- 0
          simobscomb$simAUCtrap <- 0
        }
        simobscomb$AUCobs <- max(simobscomb$obsAUCtrap)
        simobscomb$AUCsim <- max(simobscomb$simAUCtrap)
        simobscomb$calcAUC <- max(simobscomb$AUC)
        if (min(simobscomb$time) <= simobscomb$explen[1]*1.03)
        {
          simobscomb$Cmaxobs <- max(simobscomb$obsconc)
          simobscomb$Cmaxsim <- max(simobscomb$simconc)
        } else {
          simobscomb$Cmaxobs <- 0
          simobscomb$Cmaxsim <- 0
        }
        simobslist[[i]] <- simobscomb
      }

Calculate performance statistics

    for(i in 1:length(simobslist))
      if (nrow(simobslist[[i]])>0)
      {
        simobscomb <- simobslist[[i]]
        unique_scenarios$RSQD[i] <- 1 - (
          sum((simobscomb$obsconc - simobscomb$simconc)^2) /
          sum((simobscomb$obsconc-mean(simobscomb$obsconc))^2)
          )
        unique_scenarios$RMSE[i] <-
          sqrt(mean((simobscomb$simconc - simobscomb$obsconc)^2))
        unique_scenarios$AIC[i] <-
          nrow(simobscomb)*(
            log(2*pi) + 1 +
            log((sum((simobscomb$obsconc-simobscomb$simconc)^2) /
              nrow(simobscomb)))
          ) + ((44+1)*2) #44 is the number of parameters from inhalation_inits.R
        simobslist[[i]] <- simobscomb
      }

Make a plot for each scenario

    for(i in 1:length(simobslist))
      if (nrow(simobslist[[i]])>0)
      {
        simobscomb <- simobslist[[i]]
        obvpredplot <- ggplot(simobscomb, aes(x = simconc, y = obsconc)) +
          geom_point() +
          geom_abline() +
          xlab("Simulated Concentrations (uM)") +
          ylab("Observed Concentrations (uM)") +
          ggtitle(paste0(
            unique_scenarios$PREFERRED_NAME[i],
            " (",
            unique_scenarios$CONC_SPECIES[i],
            ", ",
            round(as.numeric(unique_scenarios$DOSE[i]), digits = 2),
            unique_scenarios$DOSE_U[i],
            " for ",
            round(unique_scenarios$EXP_LENGTH[i]*24, digits = 2),
            "h in ",
            unique_scenarios$SAMPLING_MATRIX[i], ")")) +
          theme_bw() +
          theme(plot.title = element_text(face = 'bold', size = 20),
            axis.title.x = element_text(face = 'bold', size = 20),
            axis.text.x = element_text(size=16),
            axis.title.y = element_text(face = 'bold', size = 20),
            axis.text.y = element_text(size = 16),
            legend.title = element_text(face = 'bold', size = 16),
            legend.text = element_text(face = 'bold',size = 14))
        obvpredlist[[i]] <- obvpredplot
      }

    simobsfull <- do.call("rbind",simobslist)
    simobsfullrat <- subset(simobsfull, simobsfull$species == "Rat")
    simobsfullhum <- subset(simobsfull, simobsfull$species == "Human")
    unique_scenarios <- subset(unique_scenarios,!is.na(unique_scenarios$RSQD))

### Creation of simulated concentration/time plots

    for (i in 1:length(plist))
    {
      plist[[i]] <- plist[[i]] +
        geom_text(
          x = Inf,
          y = Inf,
          hjust = 1.3,
          vjust = 1.3,
    #      size = 6,
          label = paste0(
            "RMSE: ",
            round(unique_scenarios$RMSE[i],digits = 2),
            "\nAIC: ",
            round(unique_scenarios$AIC[i],digits = 2)))# +
    #    theme(
    #      plot.title = element_text(face = 'bold', size = 15),
    #      axis.title.x = element_text(face = 'bold', size = 20),
    #      axis.text.x = element_text(size=16),
    #      axis.title.y = element_text(face = 'bold', size = 20),
    #      axis.text.y = element_text(size = 16),
    #      legend.title = element_text(face = 'bold', size = 16),
    #      legend.text = element_text(face = 'bold',size = 14))
    }

### Regressions

Other analytics including linear regression on overall concentration vs. time observed vs. predicted

    table(unique_scenarios$CONC_SPECIES)

    ##
    ## Human   Rat
    ##    72    65

    nrow(simobsfull) - nrow(simobsfull[
      !is.na(simobsfull$simconc) &
      simobsfull$simconc > 0 &
      simobsfull$obsconc > 0,])

    ## [1] 575

    pmiss <- (nrow(simobsfull) -
      nrow(simobsfull[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0,])) /
      nrow(simobsfull) * 100
    missdata <- (simobsfull[
      is.na(simobsfull$simconc) |
      simobsfull$simconc <= 0 |
      simobsfull$obsconc <= 0,])
    t0df <- simobsfull[simobsfull$obstime == 0,]
    lmall <- lm(
    #log transforms:
      log10(simobsfull$obsconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0]) ~
    #log transforms:
      log10(simobsfull$simconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0]))
    #Linear binned 1
    lmsub1 <- lm(
      simobsfull$obsconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc < 0.1] ~
      simobsfull$simconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc < 0.1])
    #Linear binned 2
    lmsub2 <- lm(
      simobsfull$obsconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc >= 0.1 &
        simobsfull$obsconc < 10] ~
      simobsfull$simconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc >= 0.1 &
        simobsfull$obsconc < 10])
    #Linear binned 3
    lmsub3 <- lm(
      simobsfull$obsconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc >= 10] ~
      simobsfull$simconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc >= 10])
    lmrat <- lm(
      log10(simobsfullrat$obsconc[
        !is.na(simobsfullrat$simconc) &
        simobsfullrat$simconc > 0 &
        simobsfullrat$obsconc > 0]) ~
      log10(simobsfullrat$simconc[
        !is.na(simobsfullrat$simconc) &
        simobsfullrat$simconc > 0 &
        simobsfullrat$obsconc > 0]))
    unique(simobsfullrat$chem)

    ##  [1] "1,1-Dichloroethylene"               "1,2-Dichloroethane"
    ##  [3] "1,2-Dichloropropane"                "1,3-Butadiene"
    ##  [5] "2,2-Dichloro-1,1,1-trifluoroethane" "Acrylonitrile"
    ##  [7] "Benzene"                            "Carbon tetrachloride"
    ##  [9] "Chloroform"                         "Decane"
    ## [11] "Ethylbenzene"                       "Furan"
    ## [13] "Isopropanol"                        "Methanol"
    ## [15] "Nonane"                             "Octane"
    ## [17] "Pyrene"                             "Styrene"
    ## [19] "Tetrachloroethylene"                "Toluene"
    ## [21] "Trichloroethylene"                  "n-Hexane"

    lmhum <- lm(
      log10(simobsfullhum$obsconc[
        !is.na(simobsfullhum$simconc) &
        simobsfullhum$simconc > 0 &
        simobsfullhum$obsconc > 0]) ~
      log10(simobsfullhum$simconc[
        !is.na(simobsfullhum$simconc) &
        simobsfullhum$simconc > 0 &
        simobsfullhum$obsconc > 0]))
    unique(simobsfullhum$chem)

    ##  [1] "1,1,1,2-Tetrafluoroethane"
    ##  [2] "1,1,1-Trichloroethane"
    ##  [3] "1,1,2-Trichloro-1,2,2-trifluoroethane"
    ##  [4] "1,2,4-Trimethylbenzene"
    ##  [5] "1,3-Butadiene"
    ##  [6] "1,4-Dioxane"
    ##  [7] "2-Butoxyethanol"
    ##  [8] "2H-Perfluoropropane"
    ##  [9] "Benzene"
    ## [10] "Bromotrifluoromethane"
    ## [11] "Chlorobenzene"
    ## [12] "Dichlorodifluoromethane"
    ## [13] "Dichloromethane"
    ## [14] "Ethanol"
    ## [15] "Ethyl T-butyl ether"
    ## [16] "Ethylbenzene"
    ## [17] "Isopropanol"
    ## [18] "Methyl ethyl ketone"
    ## [19] "Methyl tert-butyl ether"
    ## [20] "N-Methyl-2-pyrrolidone"
    ## [21] "Styrene"
    ## [22] "Tetrachloroethylene"
    ## [23] "Tetrahydrofuran"
    ## [24] "Trichloroethylene"
    ## [25] "Vinyl chloride"
    ## [26] "tert-Amyl methyl ether"

    concregslope <- summary(lmall)$coef[2,1]
    concregr2 <- summary(lmall)$r.squared
    concregrmse <- sqrt(mean(lmall$residuals^2))
    totalrmse <- sqrt(mean((
      log10(simobsfull$simconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0]) -
      log10(simobsfull$obsconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0]))^2,
       na.rm = T))
    totalmae <- mean(abs(
      log10(simobsfull$simconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0]) -
      log10(simobsfull$obsconc[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0])),
      na.rm = T)
    totalaic <- nrow(
      simobsfull[
        !is.na(simobsfull$simconc) &
        simobsfull$simconc >0 &
        simobsfull$obsconc >
        0,]) *
      (log(2*pi) +
         1 +
         log((sum(
           (simobsfull$obsconc[
             !is.na(simobsfull$simconc) &
             simobsfull$simconc > 0 &
             simobsfull$obsconc > 0] -
           simobsfull$simconc[
             !is.na(simobsfull$simconc) &
             simobsfull$simconc > 0 &
             simobsfull$obsconc > 0])^2,
           na.rm=T) /
         nrow(simobsfull[
           !is.na(simobsfull$simconc) &
           simobsfull$simconc > 0 &
           simobsfull$obsconc > 0,])))) +
      ((44+1)*2) #44 is the number of parameters from inhalation_inits.R
    mispred <- table(abs(
      log10(simobsfull$simconc) -
      log10(simobsfull$obsconc))>2 &
      simobsfull$simconc>0)
    mispred[2]

    ## TRUE
    ##  134

    mispred[2] / nrow(simobsfull[
      !is.na(simobsfull$simconc) &
        simobsfull$simconc >0 &
        simobsfull$obsconc > 0,])*100

    ##     TRUE
    ## 8.328154

    overpred <- table(
      log10(simobsfull$simconc) -
      log10(simobsfull$obsconc)>2 &
      simobsfull$simconc>0)
    overpred[2]

    ## TRUE
    ##   10

    overpred[2] / nrow(simobsfull[
      !is.na(simobsfull$simconc) &
      simobsfull$simconc >0 &
      simobsfull$obsconc > 0,])*100

    ##     TRUE
    ## 0.621504

    underpred <- table(
      log10(simobsfull$obsconc) -
      log10(simobsfull$simconc)>2 &
      simobsfull$simconc>0)
    underpred[2]

    ## TRUE
    ##  124

    underpred[2] / nrow(simobsfull[
      !is.na(simobsfull$simconc) &
      simobsfull$simconc >0 &
      simobsfull$obsconc > 0,])*100

    ##    TRUE
    ## 7.70665

    mispredhalf <- table(abs(
      log10(simobsfull$simconc) -
      log10(simobsfull$obsconc))>0.5 &
      simobsfull$simconc>0)
    mispredhalf[2]

    ## TRUE
    ##  675

    mispredhalf[2] / nrow(simobsfull[
      !is.na(simobsfull$simconc) &
      simobsfull$simconc >0 &
      simobsfull$obsconc > 0,])*100

    ##     TRUE
    ## 41.95152

    overpredhalf <- table(
      log10(simobsfull$simconc) -
      log10(simobsfull$obsconc)>0.5 &
      simobsfull$simconc>0)
    overpredhalf[2]

    ## TRUE
    ##  290

    overpredhalf[2] / nrow(simobsfull[
      !is.na(simobsfull$simconc) &
      simobsfull$simconc >0 &
      simobsfull$obsconc > 0,])*100

    ##     TRUE
    ## 18.02362

    underpredhalf <- table(
      log10(simobsfull$obsconc) -
      log10(simobsfull$simconc)>0.5 &
      simobsfull$simconc>0)
    underpredhalf[2]

    ## TRUE
    ##  385

    underpredhalf[2] / nrow(simobsfull[
      !is.na(simobsfull$simconc) &
      simobsfull$simconc > 0 &
      simobsfull$obsconc > 0,])*100

    ##     TRUE
    ## 23.92791

    chemunderpred <- subset(simobsfull,
      log10(simobsfull$simconc) -
      log10(simobsfull$obsconc) < 0 &
      simobsfull$simconc > 0)
    table(chemunderpred$chemclass) / table(simobsfull$chemclass)*100

    ##
    ##                      Alcohol        Aliphatic hydrocarbon
    ##                    36.666667                    16.438356
    ##         Aromatic hydrocarbon                        Ether
    ##                    43.891403                    45.967742
    ## Fluorinated organic compound Halogenated organic compound
    ##                     9.309309                    47.285887
    ##                        Other
    ##                    65.236052

## TABLE AND PLOT GENERATION

### Concentration vs. time

    # Create pdfs of simulated concentration-time plots against observed c-t values
    pdf("simdataplots.pdf")
    for (i in 1:length(plist)) {
      print(plist[[i]])
    }
    dev.off()

    # Create pdfs of observed vs. predicted concentration plots
    pdf("obvpredplots.pdf", width = 10, height = 10)
    for (i in 1:length(obvpredlist)) {
      print(obvpredlist[[i]])
    }
    dev.off()

### Figure 2: overall observed vs. predicted plot

    fig2 <- ggplot(
      data = simobsfull[
        simobsfull$simconc > 0 &
        simobsfull$obsconc > 0,],
      aes(x = log10(simconc), y = log10(obsconc))) +
      geom_point(
        color = ifelse(
          abs(
            log10(simobsfull[
              simobsfull$simconc > 0 &
              simobsfull$obsconc > 0,]$simconc) -
            log10(simobsfull[
              simobsfull$simconc > 0 &
              simobsfull$obsconc > 0,]$obsconc)) >2,
          'red',
          'black')) +
      geom_abline() +
      xlab("Log(Simulated Concentrations)") +
      ylab("Log(Observed Concentrations)") +
      theme_bw() +
      geom_smooth(method = 'lm',se = F, aes(color = 'Overall')) +
      geom_smooth(method = 'lm', se = F, aes(color = species)) +
      geom_text(
        x = Inf,
        y = -Inf,
        hjust = 1.05,
        vjust = -0.15,
    #    size = 6,
        label = paste0(
          "Regression slope: ",
          round(summary(lmall)$coef[2,1],digits = 2),
          "\nRegression R^2: ",
          round(summary(lmall)$r.squared,digits = 2),
          "\nRegression RMSE: ",
          round(sqrt(mean(lmall$residuals^2)),digits = 2),
          "\nRMSE (Identity): ",
          round(totalrmse,digits = 2),
          "\n% Missing:",
          round(pmiss, digits = 2), "%")) +
      geom_text(
        data = simobsfull[
          abs(log10(simobsfull$simconc) - log10(simobsfull$obsconc))>7 &
          simobsfull$simconc>0 & simobsfull$obsconc > 0,],
        aes(label = paste(chem,species,matrix)),
        fontface = 'bold',
        check_overlap = T,
    #    size = 3.5,
        hjust = 0.5,
        vjust = -0.8) +
      scale_color_discrete(name = 'Species', breaks = c("Overall","Human","Rat")) #+
    #  theme(
    #    plot.title = element_text(face = 'bold', size = 15),
    #    axis.title.x = element_text(face = 'bold', size = 20),
    #    axis.text.x = element_text(size=16),
    #    axis.title.y = element_text(face = 'bold', size = 20),
    #    axis.text.y = element_text(size = 16),
    #    legend.title = element_text(face = 'bold', size = 16),
    #    legend.text = element_text(face = 'bold',size = 14))
    fig2 #Display plot in R

    ## `geom_smooth()` using formula 'y ~ x'
    ## `geom_smooth()` using formula 'y ~ x'

    #pdf("Figure2.pdf", width = 10, height = 10)
    #print(fig2)
    #dev.off()

### Create and read out plots of overall cvt, cmax, and auc observed vs. pred

    # Create data and run calculations for populating plots
    cmaxfull <- subset(simobsfull, !duplicated(simobsfull$AUCobs) & simobsfull$Cmaxobs != 0)
    cmaxobs <- cmaxfull$Cmaxobs
    cmaxsim <- cmaxfull$Cmaxsim
    cmaxobs <- cmaxobs[!is.nan(cmaxsim)]
    cmaxsim <- cmaxsim[!is.nan(cmaxsim)]
    cmaxsim[!is.finite(log10(cmaxsim))] <- NA
    cmaxlm <- lm(log10(cmaxobs)~log10(cmaxsim), na.action = na.exclude)
    cmaxvcbkg <- subset(cmaxfull,
      paste(
        cmaxfull$chem,
        cmaxfull$dose,
        cmaxfull$explen,
        cmaxfull$species,
        cmaxfull$matrix) %in%
      paste(
        t0df$chem,
        t0df$dose,
        t0df$explen,
        t0df$species,
        t0df$matrix))
    cmaxvcbkg$cmaxcbkgratio <- cmaxvcbkg$Cmaxobs / cmaxvcbkg$obsconc
    cmaxvcbkg$adjustedCmaxsim <- cmaxvcbkg$Cmaxsim - cmaxvcbkg$obsconc
    aucfull <-subset(simobsfull,
      !duplicated(simobsfull$AUCobs) &
      simobsfull$AUCobs != 0)
    aucobs <- aucfull$AUCobs
    aucsim <- aucfull$AUCsim
    aucobs <- aucobs[!is.nan(aucsim)]
    aucsim <- aucsim[!is.nan(aucsim)]
    aucsim[!is.finite(log10(aucsim))] <- NA
    auclm <- lm(log10(aucobs)~log10(aucsim), na.action = na.exclude)
    cmaxslope <- summary(cmaxlm)$coef[2,1]
    cmaxrsq <- summary(cmaxlm)$r.squared
    totalrmsecmax <- sqrt(mean((log10(cmaxfull$Cmaxsim) -
      log10(cmaxfull$Cmaxobs))^2, na.rm = T))
    cmaxmiss <- nrow(cmaxfull[
      abs(log10(cmaxfull$Cmaxsim) -
      log10(cmaxfull$Cmaxobs)) > 1,])
    cmaxmissp <- nrow(cmaxfull[
      abs(log10(cmaxfull$Cmaxsim) -
      log10(cmaxfull$Cmaxobs)) > 1,]) /
      nrow(cmaxfull) * 100
    cmaxmisschem <- table(cmaxfull[
      abs(log10(cmaxfull$Cmaxsim) -
      log10(cmaxfull$Cmaxobs)) > 1,]$chem)
    aucslope <- summary(auclm)$coef[2,1]
    aucrsq <- summary(auclm)$r.squared
    totalrmseauc <- sqrt(mean((
      log10(aucfull$AUCsim) -
      log10(aucfull$AUCobs))^2, na.rm = T))
    aucmiss <- nrow(aucfull[
      abs(log10(aucfull$AUCsim) -
      log10(aucfull$AUCobs)) > 1,])
    aucmissp <- nrow(aucfull[
      abs(log10(aucfull$AUCsim) -
      log10(aucfull$AUCobs)) > 1,]) /
      nrow(aucfull) * 100
    aucmisschem <- table(aucfull[
      abs(log10(aucfull$AUCsim) -
      log10(aucfull$AUCobs)) > 1,]$chem)

### Figure 4: Cmax and AUC observed vs. Predicted Values

    cmaxp <- ggplot(data = cmaxfull, aes(x = log10(Cmaxsim), y = log10(Cmaxobs))) +
      geom_point(color =
        ifelse(abs(log10(cmaxfull$Cmaxsim)  -log10(cmaxfull$Cmaxobs))>=1, "red","black"))  +
      geom_abline()  +
      xlab("Log(Simulated Max Concentration)") +
      ylab("Log(Observed Max Concentration)") +
      theme_bw() +
      geom_smooth(method = 'lm', se = F, aes(color = 'Overall')) +
      geom_smooth(method = 'lm', se = F, aes(color = species)) +
      geom_text(x = Inf,
        y = -Inf,
        hjust = 1.05,
        vjust = -0.15,
    #    size = 6,
        label = paste0("Regression slope: ",
          round(summary(cmaxlm)$coef[2,1],digits = 2),
          "\nRegression R^2: ",
          round(summary(cmaxlm)$r.squared,digits = 2))) +
      geom_text_repel(
        data = cmaxfull[
          (log10(cmaxfull$Cmaxsim)-log10(cmaxfull$Cmaxobs))>=1 &
          log10(cmaxfull$Cmaxsim) > 2,],
        aes(label = paste(chem,species,matrix)),
        force = 2,
     #   size = 5.3,
        fontface = 'bold',
        color = 'black',
        hjust = -0.05,
        vjust = 0.5) +
      scale_y_continuous(lim = c (-1,5)) +
      scale_x_continuous(lim = c(-1,5)) +
      geom_text_repel(
        data = cmaxfull[
          (log10(cmaxfull$Cmaxsim)-log10(cmaxfull$Cmaxobs))>=1 &
          log10(cmaxfull$Cmaxsim) <= 2,],
        aes(label = paste(chem,species,matrix)),
        nudge_x = 0.0,
        nudge_y = -0.2,
        force = 2,
    #    size = 5.3,
        fontface = 'bold',
        color = 'black',
        hjust = -0.05,
        vjust = 0.5) +
      geom_text(
        data = cmaxfull[
          (log10(cmaxfull$Cmaxsim)-log10(cmaxfull$Cmaxobs))<=-1,],
        aes(label = paste(chem,species,matrix)),
    #    size = 5.3,
        fontface = 'bold',
        color = 'black',
        hjust = 0.5,
        vjust = -0.7) +
      scale_color_discrete(
        name = 'Species',
        breaks = c("Overall","Human","Rat")) #+
    #  theme(plot.title = element_text(face = 'bold', size = 10),
    #    axis.title.x = element_text(face = 'bold', size = 10),
    #    axis.text.x = element_text(size=8),
    #    axis.title.y = element_text(face = 'bold', size = 10),
    #    axis.text.y = element_text(size = 8),
    #    legend.title = element_text(face = 'bold', size = 8),
    #    legend.text = element_text(face = 'bold',size = 8))
    cmaxp

    ## `geom_smooth()` using formula 'y ~ x'
    ## `geom_smooth()` using formula 'y ~ x'

    aucp <- ggplot(
      data = aucfull,
      aes(x = log10(AUCsim), y = log10(AUCobs))) +
      geom_point(color =
        ifelse(abs(log10(aucfull$AUCsim)-log10(aucfull$AUCobs))>=1, "red","black"))  +
      geom_abline()  +
      xlab("Log(Simulated AUC)") +
      ylab("Log(Observed AUC)") +
      theme_bw() +
      geom_smooth(method = 'lm', se = F, aes(color = "Overall")) +
      geom_smooth(method = 'lm', se = F, aes(color = species)) +
      geom_text(
        x = Inf,
        y = -Inf,
        hjust = 1.05,
        vjust = -0.15,
    #    size = 6,
        label = paste0(
          "Regression slope: ",
          round(summary(auclm)$coef[2,1],digits = 2),
          "\nRegression R^2: ",
          round(summary(auclm)$r.squared,digits = 2))) +
      geom_text_repel(
        data = aucfull[(log10(aucfull$AUCsim)-log10(aucfull$AUCobs))>=1,],
        aes(label = paste(chem,species,matrix)),
    #    size = 5.3,
        fontface = 'bold',
        color = 'black',
        hjust = -0.05,
        vjust = 0.5) +
      scale_y_continuous(lim = c (-2,4)) +
      scale_x_continuous(lim = c(-2,4)) +
      geom_text(
        data = aucfull[(log10(aucfull$AUCsim)-log10(aucfull$AUCobs))<=-1,],
        aes(label = paste(chem,species,matrix)),
    #    size = 5.3,
        fontface = 'bold',
        color = 'black',
        hjust = 0.5,
        vjust = -0.8) +
      scale_color_discrete(name = 'Species', breaks = c("Overall","Human","Rat")) #+
    #  theme(
    #    plot.title = element_text(face = 'bold', size = 15),
    #    axis.title.x = element_text(face = 'bold', size = 20),
    #    axis.text.x = element_text(size=16),
    #    axis.title.y = element_text(face = 'bold', size = 20),
    #    axis.text.y = element_text(size = 16),
    #    legend.title = element_text(face = 'bold', size = 16),
    #    legend.text = element_text(face = 'bold',size = 14))
    aucp

    ## `geom_smooth()` using formula 'y ~ x'
    ## `geom_smooth()` using formula 'y ~ x'

    #pdf("Figure4.pdf", width = 20, height = 10)
    #plot_grid(cmaxp,aucp,nrow = 1, labels = c('A','B'), label_size = 30)
    #dev.off()

### Figure 3: Separation by chemical class

    simobsfull$aggscen <- as.factor(paste(simobsfull$chem,
      simobsfull$species,
      simobsfull$matrix))
    chem.lm <- lm(
      log10(simconc) - log10(obsconc) ~
      aggscen,
      data = simobsfull[simobsfull$simconc >0 & simobsfull$obsconc > 0,])
    chem.res <- resid(chem.lm)
    # Number of observations per chemical class
    numpt <- simobsfull[simobsfull$simconc >0 & simobsfull$obsconc > 0,] %>%
      group_by(chemclass) %>% summarize(n = paste("n =", length(simconc)))
    fig3 <- ggplot(
      data = simobsfull[simobsfull$simconc >0 & simobsfull$obsconc > 0,],
      aes(x = aggscen, y = log10(simconc)-log10(obsconc), fill = chemclass)) +
      geom_boxplot() +
      geom_hline(yintercept = 0) +
      geom_hline(yintercept = 2, linetype = 2)+
      geom_hline(yintercept = -2, linetype = 2)+
      xlab("Exposure Scenario") +
      ylab("Log(Simulated Concentration)-\nLog(Observed Concentration)\n") +
      facet_wrap(vars(chemclass), scales = 'free_x', nrow = 1) + #35 by 12 for poster
      theme_bw() +
      geom_text(
        data = numpt,
        aes(x = Inf, y = -Inf, hjust = 1.05, vjust = -0.5, label = n),
        size = 10,
        colour = 'black',
        inherit.aes = F,
        parse = F) +
      theme(
        axis.text.x = element_text(angle = 90, hjust = 1,vjust=0.5,size = 20, face = 'bold'),
        strip.text.x = element_text(face = 'bold', size = 24),
        legend.position = 'none',
        axis.title.x = element_text(face = 'bold', size = 30),
        axis.title.y = element_text(face = 'bold', size = 30),
        axis.text.y = element_text(face = 'bold',size = 25, color = 'black'))
    fig3
    #pdf("Figure3.pdf", width = 40, height = 13)
    #print(fig3)
    #dev.off()

### Figures S1A-S1D: Separation by time quartile and physicochemical properties

    figs1a <- ggplot(
        data = simobsfull[simobsfull$simconc >0 & simobsfull$obsconc > 0,],
        aes(x = tquart, y = log10(simconc)-log10(obsconc))) +
      geom_boxplot()+
      geom_hline(yintercept = 0)+
      geom_hline(yintercept = 2, linetype = 2)+
      geom_hline(yintercept = -2, linetype = 2)+
      xlab("\nTime Quartile\n") +
      ylab("Log(Simulated Concentration)-\nLog(Observed Concentration)\n") +
      theme_bw()+
      theme(
        axis.text.x = element_text(size = 20, face = 'bold'),
        strip.text.x = element_text(face = 'bold', size = 20),
        legend.position = 'none',
        axis.title.x = element_text(face = 'bold', size = 20),
        axis.title.y = element_text(face = 'bold', size = 20),
        axis.text.y = element_text(size = 20, face = 'bold'))
    figs1a
    figs1b <- ggplot(
        data = simobsfull[simobsfull$simconc >0 & simobsfull$obsconc > 0,],
        aes(x = mw, y = log10(simconc)-log10(obsconc))) +
      geom_point()+
      geom_hline(yintercept = 0)+
      geom_hline(yintercept = 2, linetype = 2)+
      geom_hline(yintercept = -2, linetype = 2)+
      xlab("\nMolecular Weight (g/mol)\n") +
      ylab("\nLog(Simulated Concentration)-\nLog(Observed Concentration)\n") +
      theme_bw()+
      theme(
        axis.text.x = element_text(size = 20, face = 'bold'),
        strip.text.x = element_text(face = 'bold', size = 20),
        legend.position = 'none',
        axis.title.x = element_text(face = 'bold', size = 20),
        axis.title.y = element_text(face = 'bold', size = 20),
        axis.text.y = element_text(size = 20, face = 'bold'))
    figs1b
    figs1c <- ggplot(
        data = simobsfull[simobsfull$simconc >0 & simobsfull$obsconc > 0,],
        aes(x = logp, y = log10(simconc)-log10(obsconc))) +
      geom_point()+
      geom_hline(yintercept = 0)+
      geom_hline(yintercept = 2, linetype = 2)+
      geom_hline(yintercept = -2, linetype = 2)+
      xlab("\nLog P") +
      ylab("Log(Simulated Concentration)-\nLog(Observed Concentration)\n") +
      theme_bw() +
      theme(
        axis.text.x = element_text(size = 20, face = 'bold'),
        strip.text.x = element_text(face = 'bold', size = 20),
        legend.position = 'none',
        axis.title.x = element_text(face = 'bold', size = 20),
        axis.title.y = element_text(face = 'bold', size = 20),
        axis.text.y = element_text(size = 20, face = 'bold'))
    figs1c
    figs1d <- ggplot(
        data = simobsfull[simobsfull$simconc >0 & simobsfull$obsconc > 0,],
        aes(x = sol, y = log10(simconc)-log10(obsconc))) +
      geom_point()+
      geom_hline(yintercept = 0)+
      geom_hline(yintercept = 2, linetype = 2)+
      geom_hline(yintercept = -2, linetype = 2)+
      xlab("\nSolubility (mol/L)") +
      ylab("\nLog(Simulated Concentration)-\nLog(Observed Concentration)\n") +
      scale_x_log10()+
      theme_bw() +
      theme(
        axis.text.x = element_text(size = 20, face = 'bold'),
        strip.text.x = element_text(face = 'bold', size = 20),
        legend.position = 'none',
        axis.title.x = element_text(face = 'bold', size = 20),
        axis.title.y = element_text(face = 'bold', size = 20),
        axis.text.y = element_text(size = 20, face = 'bold'))
    figs1d
    #pdf("FigureS1.pdf", width = 20, height = 20)
    plot_grid(figs1a,figs1b,figs1c,figs1d,nrow = 2, labels = c('A','B','C','D'), label_size = 30)
    #dev.off()

### Supplemental Table 2: Leave-one-out Chemical Sensitivity Analysis

    senschem <- list()
    sensslope <- list()
    sensrsq <- list()
    sensregrmse <- list()
    senstotalrmse <- list()
    senspmiss <- list()
    senscmaxslope <- list()
    senscmaxrsq <- list()
    senstotalrmsecmax <- list()
    sensaucslope <- list()
    sensaucrsq <- list()
    senstotalrmseauc <- list()
    for (i in 1:nrow(simobsfull))
    {
      simobsfullsens <- subset(simobsfull,simobsfull$chem != simobsfull$chem[i])
      senschem[i] <- as.character(simobsfull$chem[i])
      senslm <- lm(
        log10(simobsfullsens$obsconc[
          !is.na(simobsfullsens$simconc) &
          simobsfullsens$simconc > 0 &
          simobsfullsens$obsconc > 0])
        log10(simobsfullsens$simconc[
          !is.na(simobsfullsens$simconc) &
          simobsfullsens$simconc >0 &
          simobsfullsens$obsconc > 0]))
      sensslope[i] <- round(summary(senslm)$coef[2,1],digits = 2)
      sensrsq[i] <- round(summary(senslm)$r.squared,digits = 2)
      sensregrmse[i] <- round(sqrt(mean(lm$residuals^2)),digits = 2)
      senstotalrmse[i] <- round(sqrt(mean((
        log10(simobsfullsens$simconc[
          !is.na(simobsfullsens$simconc) &
          simobsfullsens$simconc >0 &
          simobsfullsens$obsconc > 0]) -
        log10(simobsfullsens$obsconc[
          !is.na(simobsfullsens$simconc) &
            simobsfullsens$simconc >0 &
            simobsfullsens$obsconc > 0]))^2,
        na.rm = T)), digits = 2)
      senspmiss[i] <- round((nrow(simobsfullsens) -
        nrow(simobsfullsens[
          !is.na(simobsfullsens$simconc) &
          simobsfullsens$simconc >0 &
          simobsfullsens$obsconc > 0,])) / nrow(simobsfullsens) * 100,
        digits = 2)
      senscmaxfull <- subset(simobsfullsens, !duplicated(simobsfullsens$Cmaxobs))
      senscmaxlm <- lm(
        log10(senscmaxfull$Cmaxobs[senscmaxfull$Cmaxobs>0]) ~
        log10(senscmaxfull$Cmaxsim[senscmaxfull$Cmaxobs>0]),
        na.action = na.exclude)
      sensaucfull <-subset(simobsfullsens, !duplicated(simobsfullsens$AUCobs))
      sensauclm <- lm(
        log10(aucfull$AUCobs[aucfull$AUCobs>0]) ~
        log10(aucfull$AUCsim[aucfull$AUCobs>0]),
        na.action = na.exclude)
      senscmaxslope[i] <- round(summary(senscmaxlm)$coef[2,1],digits = 2)
      senscmaxrsq[i] <- round(summary(senscmaxlm)$r.squared,digits = 2)
      senstotalrmsecmax[i] <- sqrt(mean((log10(senscmaxfull$Cmaxsim[senscmaxfull$Cmaxobs>0]) - log10(senscmaxfull$Cmaxobs[senscmaxfull$Cmaxobs>0]))^2, na.rm = T))
      sensaucslope[i] <- round(summary(sensauclm)$coef[2,1],digits = 2)
      sensaucrsq[i] <- round(summary(sensauclm)$r.squared,digits = 2)
      senstotalrmseauc[i] <- sqrt(mean((log10(sensaucfull$AUCsim[sensaucfull$AUCobs>0]) - log10(sensaucfull$AUCobs[sensaucfull$AUCobs>0]))^2, na.rm = T))
    }
    sensitivitydf <- data.frame(Chemical <- as.character(senschem),
                                sensSlope <- as.numeric(sensslope),
                                sensRsq <- as.numeric(sensrsq),
                                sensRegrmse <- as.numeric(sensregrmse),
                                sensTotrmse <- as.numeric(senstotalrmse),
                                sensPmiss <- as.numeric(senspmiss),
                                sensCmaxslope <- as.numeric(senscmaxslope),
                                sensCmaxrsq <- as.numeric(senscmaxrsq),
                                sensCmaxrmse <- as.numeric(senstotalrmsecmax),
                                sensAUCslope <- as.numeric(sensaucslope),
                                sensAUCrsq <- as.numeric(sensaucrsq),
                                sensAUCrmse <- as.numeric(senstotalrmseauc),
                                stringsAsFactors=FALSE)
    sensitivitydf <- subset(sensitivitydf,!duplicated(sensitivitydf$Chemical....as.character.senschem.))
    names(sensitivitydf) <- c('Chemical Dropped','Regression Slope','Regression R^2','Regression RMSE','Orthogonal RMSE', 'Percent Data Censored','Cmax Regression Slope','Cmax Regression R^2','Cmax Orthogonal RMSE','AUC Regression Slope','AUC Regression R^2','AUC Orthogonal RMSE')
    notdropped <- c('None',concregslope,concregr2,concregrmse,totalrmse,pmiss,cmaxslope,cmaxrsq,totalrmsecmax,aucslope,aucrsq,totalrmseauc)
    sensitivitydf <- rbind(notdropped, sensitivitydf)
    sensitivitydf[,-1] <- sapply(sensitivitydf[,-1],as.numeric)
    sensitivitydf[,-1] <- round(sensitivitydf[,-1],2)
      # Clean up and write file
    rm(chem.lm, obvpredplot, p, pdata1, plot.data, plots, relconc, sensaucfull, sensauclm, sensaucrsq, sensaucslope, senschem, senscmaxfull, senscmaxlm, senscmaxrsq, senscmaxslope, senslm, senspmiss, sensregrmse, sensrsq, sensslope, senstotalrmse, senstotalrmseauc, senstotalrmsecmax, solve, AUCrmse, AUCrsq, AUCslope, chem.res, Chemical, Cmaxrmse, Cmaxrsq, Cmaxslope, colors, count, i, j, k, met_col, name, name1, Pmiss, Regrmse, Rsq, Slope, rem, Totrmse)

    write.csv(sensitivitydf, 'supptab2.csv',row.names = F)

### Supplemental Table 1

    supptab1 <- subset(unique_scenarios, !duplicated(unique_scenarios$PREFERRED_NAME) | !duplicated(unique_scenarios$SOURCE_CVT) | !duplicated(unique_scenarios$CONC_SPECIES))
    for(i in 1:nrow(supptab1)){
      tryCatch({
        supptab1$Metabolism_Source[i] <- met_data$SOURCE_MET[met_data$DTXSID %in% supptab1$DTXSID[i] & met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
        supptab1$Log_P[i] <- met_data$OCTANOL_WATER_PARTITION_LOGP_OPERA_PRED[met_data$DTXSID %in% supptab1$DTXSID[i]& met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
        supptab1$Solubility[i] <- met_data$WATER_SOLUBILITY_MOL.L_OPERA_PRED[met_data$DTXSID %in% supptab1$DTXSID[i]& met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
        supptab1$Blood_Air_Partition_Coefficient[i] <- met_data$CALC_PBA[met_data$DTXSID %in% supptab1$DTXSID[i]& met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
        supptab1$Chem_Class[i] <- met_data$CHEM_CLASS[met_data$DTXSID %in% supptab1$DTXSID[i] & met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
        supptab1$Species[i] <- met_data$SPECIES[met_data$DTXSID %in% supptab1$DTXSID[i] & met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
        supptab1$Vmax[i] <- met_data$VMAX[met_data$DTXSID %in% supptab1$DTXSID[i] & met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
        supptab1$Km[i] <- met_data$KM[met_data$DTXSID %in% supptab1$DTXSID[i] & met_data$SPECIES %in% supptab1$CONC_SPECIES[i]]
      }, error = function(e){})
    }
    supptab1 <- supptab1[c('PREFERRED_NAME','DTXSID','CASRN','Chem_Class','AVERAGE_MASS','Log_P','Solubility','Blood_Air_Partition_Coefficient','Species','Vmax','Km','Metabolism_Source','SOURCE_CVT')]
    names(supptab1) <- c('Chemical','DTXSID','CASRN','CAMEO Chemical Class','Molecular Weight (g/mol)','Log P','Solubility (mol/L)','Blood Air Partition Coefficient','Available Species Data','Vmax (pmol/min/10^6 cells)','KM (uM)','Metabolism Data Source','Concentration-Time Data Source')
    write.csv(supptab1, "supptab1.csv", row.names = F)