PROGRAM CPF Lifestage ! CPF Lifestage 2015 MR_preg.csl ! Orig from Timchalk 2002 ! By C. Timchalk, Battelle PNNL, Richland, WA, USA ! This is based on the final version of the model developed for Dow Agrosciences ! the parameters were experimentally determined or optimized against ! available data sets. See associated data file for needed PROC files ! Updates: ! Metabolic parameters to incorporate scaling ! factors based on experimental age-dependent changes (Smith et al., 2010) ! Amount of tissue esterase (umole) based on ! age-dependent scaling using available published results ! Equation to calc bodywt from age (Hinderliter) ! Incorporated dynamic age-dependent changes to physiology and a generalized ! framework for human extrapolation (Luecke 2007 & Young 2009) ! Changed QCC flow method to a summation of QC from each compartment. ! GI, diaphragm, dermal and brain metabolism ! Variability estimation added to compartment volumes and enzymology ! Based on Local Sensitivity Analysis results (Poet and Hinderliter) ! Changes to model in January of 2014... ! code was added to allow for dosing of amount via the oral route (vs /kg) (Poet) ! in general, the amount dose variables were written to match the oral route !also note lines in .m files to setup parameters have been added to zero !amount dosed !Changes in model in January of 2014 to allow for repeat inhalation dosing. (Poet) !DERMAL and inhalation dosing now controlled by a pulse. Instructions in that area of code (Poet) !Changes in January of 2015 to include pregnancy (Poet) !########################################################################

INITIAL

VARIABLE TIME=0.0 ! HR CONSTANT AGE0=0.0 ! Initial age (D for rats & Y for humans) CONSTANT SPECIES=0 ! Species dummy variable: 0=male rat, 1=male human CONSTANT PREG=0.0 !switch to pregnant woman CONSTANT GDSTART=0.0 !ZERO DAY OF PREGNANCY - DON'T EXCEED 275 (9 MONTHS)

CONSTANT BWSW=0.0 !Switch for age (set =0) or set (set =1) determination of BW CONSTANT BWST=0.0 !Set value of BW (kg) ! Gompertz equation parameters CONSTANT B1=0.0;CONSTANT B2=0.0;CONSTANT B3=0.0;CONSTANT B4=0.0;CONSTANT B5=0.0 CONSTANT B6=0.0;CONSTANT B7=0.0;CONSTANT B8=0.0;CONSTANT AGE1=0.0 CONSTANT AGE2=0.0;CONSTANT AGE3=0.0 CONSTANT SEX=0

! Age dependent B4 & B8 for humans (Luecke 2007) IF ((AGE0 .GE. AGE1) .AND. (AGE0 .LT. AGE2) .AND. (SPECIES .EQ. 1)) THEN B4x=B4;B8x=0 ELSE IF ((AGE0 .GE. AGE3) .AND. (SPECIES .EQ. 1)) THEN B4x=0;B8x=B8 ELSE B4x=0;B8x=0 END IF

! Initial BWT (kg) (Luecke 2007) IF (AGE0 .GE. AGE2) THEN BWTINIT=B5*EXP((B6/B7)*(1-EXP(-B7*(AGE0-AGE2))))+B8x*(AGE0-AGE3) ELSE BWTINIT=B1*EXP((B2/B3)*(1-EXP(-B3*AGE0)))+B4x*(AGE0-AGE1) END IF

!INITIALIZE SOME VARIABLES BWT=(BWTINIT*(1.-BWSW)+VFET+VPLA+VUTR+(VFI-VFINIT)+(VBLI-VBLINIT)+(VSI-VSINIT)+(VRI-VRINIT ))+BWST*BWSW BWTG=(BWTINIT*(1.-BWSW)+BWST*BWSW)*1000 ! BWT kg to grams for compartment vol calcs! Initial Height (HT: fit to CDC growth chart (human) HT=19.994+(5.5408*BWT)-(0.0671*BWT**2)+0.0003*BWT**3

! Initial compartment volumes (frac of BWT)(developed Luecke 2007 & Young 2009; Described in Smith et al., 2013) VBC=VB0+(VB1*LBWT)+(VB2*LBWT**2)+(VB3*LBWT**3)+(VB4*LBWT**4)+(VB5*LBWT**5)+(VB6*LBWT**6) ! Brain VHC=VH0+(VH1*BWTG)+(VH2*BWTG**2)+(VH3*BWTG**3)+(VH4*BWTG**4) ! Liver VBLC=VBL0+(VBL1*BWTG)+(VBL2*BWTG**2) ! Blood VFC=VF0+(VF1*BWTG)+(VF2*BWTG**2)+(VF3*BWTG**3)+(VF4*BWTG**4)+(VF5*BWTG**5)+(VF6*BWTG**6) VAC=VA0+(VA1*BWTG)+(VA2*BWTG**2)+(VA3*BWTG**3)+(VA4*BWTG**4)+(VA5*BWTG**5)+(VA6*BWTG**6) ! Adipose VKC=VK0+(VK1*BWTG)+(VK2*BWTG**2) ! Kidney (in rapid) VSPC=VSP0+(VSP1*BWTG)+(VSP2*BWTG**2) ! Spleen (in rapid) VLC=VL0+(VL1*BWTG)+(VL2*BWTG**2) ! Lung (in rapid) VGIC=VGI0!+(VGI1*BWTG)+(VGI2*BWTG**2)+(VGI3*BWTG**3) ! GI, both stomach and intestines (in rapid) VMC=VM0+(VM1*BWTG)+(VM2*BWTG**2)+(VM3*BWTG**3)+(VM4*BWTG**4) ! Muscle (in slow) VSKC=VSK0+(VSK1*BWTG)+(VSK2*BWTG**2)+(VSK3*BWTG**3)+(VSK4*BWTG**4)+(VSK5*BWTG**5) ! Skin (in slow) note - for dermal this is "external" compartment CONSTANT FATVAR = 0.0 CONSTANT VOLUNCERT = 0.0 CONSTANT KUNCERT= 0.0 CONSTANT VHCv=0.0 CONSTANT VBLv=0.0 QHCV=0.0 VFCv=GAUSS(0.,FATVAR*VFC) VFCv = RSW(VFC+VFCv .LT. 0.1*VFC, 0.1*VFC, VFCv) ! check to ensure that vol is > 0 CONSTANT VBMC=0.0 ! Bone marrow (in slow) VRC=VKC+VSPC+VLC+VGIC ! Rapid VSC=VMC+VSKC+VBMC+(VAC-VFC) ! Slow CONSTANT VDC=0.0 ! Diaphram CONSTANT VPC=0.0 ! Pancreas (in rapid) CONSTANT VINTC=0.0 ! Small intestine, for metabolism only

! Volume variability, set VOLUNCERT=0 to turn off VSCu=GAUSS(0.,VOLUNCERT*VSC) VRCu=GAUSS(0.,VOLUNCERT*VRC) VBCu=GAUSS(0.,VOLUNCERT*VSC) KPLU=GAUSS(0.,KUNCERT*KPL) !VHCu=GAUSS(0.,VOLUNCERT*VHC) !This can be used if total uncertainty is desired, or the next line to vary just hepatic volume based on P3M VHCu=GAUSS(0.,VHCv*VHC) VFCu=GAUSS(0.,VOLUNCERT*VFC) VBLCu=GAUSS(0.,VBLV*VBLC) VDCu=GAUSS(0.,VOLUNCERT*VDC) VINTCu=GAUSS(0.,VOLUNCERT*VINTC) VSCu = RSW(VSC+VSCu .LT. 0.1*VSC, 0.1*VSC, VSCu) ! check to ensure that vol is > 0 VRCu = RSW(VRC+VRCu .LT. 0.1*VRC, 0.1*VRC, VRCu) ! check to ensure that vol is > 0 VBCu = RSW(VBC+VBCu .LT. 0.1*VBC, 0.1*VBC, VBCu) ! check to ensure that vol is > 0 VHCu = RSW(VHC+VHCu .LT. 0.1*VHC, 0.1*VHC, VHCu) ! check to ensure that vol is > 0 VFCu = RSW(VFC+VFCu .LT. 0.1*VFC, 0.1*VFC, VFCu) ! check to ensure that vol is > 0 VBLCu = RSW(VBLC+VBLCu .LT. 0.1*VBLC, 0.1*VBLC, VBLCu) ! check to ensure that vol is > 0 VDCu = RSW(VDC+VDCu .LT. 0.1*VDC, 0.1*VDC, VDCu) ! check to ensure that vol is > 0 VINTCu = RSW(VINTC+VINTCu .LT. 0.1*VINTC, 0.1*VINTC, VINTCu) ! check to ensure that vol is > 0 KPLU = RSW(KPL+KPLu .LT. 0.1*KPL, 0.1*KPL, KPLu) ! check to ensure > 0

VSC=VSC+VSCu VRC=VRC+VRCu VBC=VBC+VBCu VHC=VHC+VHCu VFC=VFC+VFCuVBLC=VBLC+VBLCu VDC=VDC+VDCu VINTC=VINTC+VINTCu KPL=KPL+KPLU

! Compartment volume polynomial parameters CONSTANT VB0=0.0;CONSTANT VB1=0.0;CONSTANT VB2=0.0;CONSTANT VB3=0.0;CONSTANT VB4=0.0 CONSTANT VB5=0.0;CONSTANT VB6=0.0 CONSTANT VH0=0.0;CONSTANT VH1=0.0;CONSTANT VH2=0.0;CONSTANT VH3=0.0;CONSTANT VH4=0.0 CONSTANT VBL0=0.0;CONSTANT VBL1=0.0;CONSTANT VBL2=0.0 CONSTANT VF0=0.0;CONSTANT VF1=0.0;CONSTANT VF2=0.0;CONSTANT VF3=0.0;CONSTANT VF4=0.0 CONSTANT VF5=0.0;CONSTANT VF6=0.0 CONSTANT VA0=0.0;CONSTANT VA1=0.0;CONSTANT VA2=0.0;CONSTANT VA3=0.0;CONSTANT VA4=0.0 CONSTANT VA5=0.0;CONSTANT VA6=0.0 CONSTANT VK0=0.0;CONSTANT VK1=0.0; CONSTANT VK2=0.0 CONSTANT VSP0=0.0;CONSTANT VSP1=0.0;CONSTANT VSP2=0.0 CONSTANT VL0=0.0;CONSTANT VL1=0.0;CONSTANT VL2=0.0 CONSTANT VGI0=0.0;CONSTANT VGI1=0.0;CONSTANT VGI2=0.0;CONSTANT VGI3=0.0 CONSTANT VM0=0.0;CONSTANT VM1=0.0;CONSTANT VM2=0.0;CONSTANT VM3=0.0;CONSTANT VM4=0.0 CONSTANT VSK0=0.0;CONSTANT VSK1=0.0;CONSTANT VSK2=0.0;CONSTANT VSK3=0.0; CONSTANT VSK4=0.0;CONSTANT VSK5=0.0

! Compartment volumes (L) VB=VBC*BWT VH=VHC*BWT VBLN=VBLC*BWT !For pregnancy, blood volume is approximated by the combination of plasma and RBC, which increase over GD !VBLN is used to set to age-specific blood volume to start VAB=0.46*VBL VRN=VRC*BWTINIT VSN=VSC*BWTINIT VD=VDC*BWT VINT=VINTC*BWT VLU=VLC*BWT VFN=VFC*BWT !For pregnancy, fat increases over GD, VFN is used to set to the age-specific fat volume to start

IF (SPECIES .EQ. 0) THEN ! Log of BWT for rat brain calc LBWT=LOG(BWT) ELSE LBWT=BWT*1000 END IF

! Blood flow to each compartment (L/h/kg) CONSTANT QFC=0.0 ! To fat CONSTANT QHC=0.0 ! To liver CONSTANT QSC=0.0 ! To slow CONSTANT QBC=0.0 ! To brain CONSTANT QDC=0.0 ! To diaphram CONSTANT QRC=0.0 ! To rapid

!Variability to to activity level CONSTANT WORK= 0.0 !Work in Watts DVO2=WORK*10.1/1000.; ! Blood Flow adjustments QFCv = 0.017*DVO2*60. !QHCv = -0.19*DVO2*60. !FOR WORK, OR FOR VARIABILITY COMMENT OUT and use following line QHCvv=GAUSS(0.,QHCv*QHC) QSCv = 7.38*DVO2*60. QRCv = -0.08*DVO2*60.

! VOLUME OF EXPOSED SKIN - MODEL 1 VSKCC=VSKC*(SA/TSA) ! FRACTION SKIN TISSUE EXPOSED

! PART COEF CHLORPYRIFOS (C) MODEL 1 (POULIN, KRISHNAN; 1995)CONSTANT PFCN=0.0 ! FAT/BLOOD CONSTANT PHC=0.0 ! LIVER/BLOOD CONSTANT PRC=0.0 ! RICHLY PERFUSED/BLOOD CONSTANT PSC=0.0 ! SLOWLY PERFUSED/BLOOD CONSTANT PDC=0.0 ! DIAPHRAM/BLOOD CONSTANT PBC=0.0 ! BRAIN/BLOOD CONSTANT PBL=0.0 ! BLOOD/BLOOD CONSTANT PLU=0.0 ! LUNG/BLOOD CONSTANT PLAIR=2000 !NOT VOLATILE CONSTANT PSKL=0.0 ! THIS IS FOR EXPOSURE ONLY AND REPRESENTS QSKC/PSKC CONSTANT PPLA=0.0!Placenta CONSTANT PAFC=1 !FETAL DIFFUSION - THIS IS 0.01 IN GENTRY MODEL, 19 IN lOWE ET AL 2010

! PROTEIN BINDING CHLORPYRIFOS (C) MODEL 1 (Lowe 2009) CONSTANT FBC=0.0 ! FRAC BOUND CPF IN BLOOD CONSTANT FBO=0.0 ! FRAC BOUND CPF-oxon in blood CONSTANT FUBO=0.0 !FRAC UNBOUND CONSTANT FUBC=0.0 CONSTANT HCTN=0.0 ! HEMATOCRIT FRACTION RBC

! PART COEF OXON (O) MODEL 2 (Lowe 2009) CONSTANT PFON=0.0 ! FAT/BLOOD CONSTANT PHO=0.0 ! LIVER/BLOOD CONSTANT PRO=0.0 ! RICHLY PERFUSED/BLOOD CONSTANT PSO=0.0 ! SLOWLY PERFUSED/BLOOD CONSTANT PDO=0.0 ! DIAPHRAM/BLOOD CONSTANT PBO=0.0 ! BRAIN/BLOOD CONSTANT PBLO=0.0 ! BLOOD/BLOOD CONSTANT PLUO=0.0 CONSTANT PLAIRO=2000 CONSTANT PSKO=0.0 CONSTANT PPLAO=0.0

! Metabolic parameters (Smith 2011, Poet 2004) CONSTANT KMHHCO=0.0 ! Hepatic Km CPF -> CPF-oxon (umol/L) CONSTANT VMHHCO=0.0 ! Hepatic Vmaxc CPF -> CPF-oxon (umol/hr/kg tissue) CONSTANT KMHCP=0.0 ! Hepatic Km CPF -> TCPy (umol/L) CONSTANT VMHCP=0.0 ! Hepatic Vmaxc CPF -> TCPy (umol/hr/kg tissue) CONSTANT KMLST=0.0 ! Hepatic Km CPF-oxon -> TCPy (umol/L) CONSTANT VML=0.0 ! Hepatic Vmaxc CPF-oxon -> TCPy (umol/hr/kg tissue)

CONSTANT VMBL1=0.0;CONSTANT VMBL2=0.0;CONSTANT VMBL3=0.0 VMBL=VMBL1/(1+EXP((VMBL2-AGE)/VMBL3)) ! Blood Vmaxc CPF-oxon -> TCPy (umol/hr/L plasma), Dynamic: logistic func MOVED FOR PREG !CONSTANT VMBL=430000 !Comment out line above AND 772 to run bootstrap wtih assigned VMBL values) CONSTANT KMBLST=0.0 ! Blood Km CPF-oxon -> TCPy (umol/L)

CONSTANT VINTOC=0.0 ! Small intestine Vmaxc of CPF -> CPF-oxon (umol/hr/kg liver) CONSTANT KMINTO=0.0 ! Small intestine Km of CPF -> CPF-oxon (umol/L) CONSTANT VINTTC=0.0 ! Small intestine Vmaxc of CPF -> TCPy (umol/hr/kg tissue) CONSTANT KMINTC=0.0 ! Small intestine Km of CPF -> TCPy (umol/L) CONSTANT VINTOXC=0.0 ! Small intestine Vmaxc of CPF-oxon -> TCPy (umol/hr/kg tissue) CONSTANT KMINTOX=0.0 ! Small intestine Km of CPF-oxon -> TCPy (umol/L)

CONSTANT VMCBCO=0.0 ! Brain Vmaxc of CPF -> CPF-oxon (umol/h/kg) CONSTANT KMBCO=0.0 ! Brain Km of CPF -> CPF-oxon (umol/L) CONSTANT VMCBCP=0.0 ! Brain Vmaxc of CPF -> TCPy (umol/h/kg) CONSTANT KMBCP=0.0 ! Brain Km of CPF -> TCPy (umol/L) CONSTANT KMBCPT=0.0 !Brain oxon ->TCPy CONSTANT VMBCPTC=0.0 !Brain oxon ->TCPy

CONSTANT VMAXOLUC=0.0 !LUNG VMAXC CPF->OXON CONSTANT KMOLU=0.0 !LUNG CPF->OXONCONSTANT VMAXTLUC=0.0 !LUNG VMAXC CPF->TCP CONSTANT KMTLU=0.0 !LUNG CPF->TCP CONSTANT VMAXPLUC=0.0 !LUNG VMAXC OXON->TCP CONSTANT KMPLUC=0.0 !LUNG OXON->TCP CONSTANT KMUC=0.87 !kMC hr-1 FURUBAYASHI et al Biol. Pharm. Bull. 2007 = 0.0145 min-1

!diaphragm metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM)copied from brain CONSTANT VMCDPCO=0.0 ! CPF -> CPF-oxon CONSTANT KMDPCO=0.0 ! Fitted to brain ChEA, 1/10 hepatic CONSTANT VMCDPCP=0.0 ! CPF -> TCPy, Extrap from Layshock 2009 unpub CONSTANT KMDPCP=0.0 ! Same as hepatic

!dermal metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM)copied from brain CONSTANT VMCDERMCO=0.0 ! CPF -> CPF-oxon CONSTANT KMDERMCO=0.0 ! Fitted to brain ChEA, 1/10 hepatic CONSTANT VMCDERMCP=0.0 ! CPF -> TCPy, Extrap from Layshock 2009 unpub CONSTANT KMDERMCP=0.0 ! Same as hepatic CONSTANT KMDERMEST=0.0 ! Km CPF-oxon -> TCPy (umol/L), same as hepatic CONSTANT VMDERMESTC=0.0 ! dermal Vmaxc CPF-oxon -> TCPy (umol/hr/kg tissue)

! Scaling Vmaxc to Vmax (umol/h) VMHHON=VMHHCO*VH ! Hepatic CPF -> CPF-oxon VMHCN=VMHCP*VH ! Hepatic CPF -> TCPy VMLSTN=VML*VH VMBLSTN=VMBL*VBL*(1-HCT) !VMLST=VMLN*VH ! Hepatic CPF-oxon -> TCPy moved to dynamic for pregnancy control VINTO=VINTOC*VINT ! Sm int. CPF -> CPF-oxon VINTT=VINTTC*VINT ! Sm int. CPF -> TCPy VINTOX=VINTOXC*VINT ! Sm int. CPF-oxon -> TCPy VMBCO=VMCBCO*VB ! Brain CPF -> CPF-oxon VMBCP=VMCBCP*VB ! Brain CPF -> TCPy VMBCPT=VMBCPTC*VB VMAXOLU=VMAXOLUC*VLU ! LUNG CPF->OXON VMAXTLU=VMAXTLUC*VLU ! LUNG CPF->TCP VMAXPLU=VMAXPLUC*VLU !LUNG OXON->TCP VMCDPO=VMCDPCO*VD !Diaphragm CPF-> oxon VMCDPP=VMCDPCP*VD !Diaphragm CPF-> TCPy VMDERMO=VMCDERMCO*VSKCC ! DERMAL CPF -> CPF-oxon VMDERMC=VMCDERMCP*VSKCC ! DERMAL CPF -> TCPy VMDERMEST=VMDERMESTC*VSKCC ! DERMAL ESTERASE OXON -> TCPy

! Enzyme turnover rates (umol hydrolysis/h/umol active sites) CONSTANT TRCE=0.0 ! ACHE CONSTANT TRBE=0.0 ! BCHE CONSTANT TRCR=0.0 ! CAE

! Enzyme activities (umol/hr/kg tissue) CONSTANT BACHE=0.0 ! BRAIN AChE CONSTANT DACHE=0.0 ! DIAPHRAGM AChE CONSTANT HACHE=0.0 ! HEPATIC AChE CONSTANT BLACHE=0.0 ! Plasma AChE CONSTANT RBCHE=0.0 ! RBC AChE CONSTANT LUACHE=0.0 ! LUNG AChE

CONSTANT BRCE=0.0 ! Brain CaE CONSTANT DACE=0.0 ! DIAPHRAGM CaE CONSTANT HECE=0.0 ! Hepatic CaE CONSTANT PLOCE=0.0 ! Plasma CaE CONSTANT LUECE=0.0 ! LUNG CaE

CONSTANT BBUCE=0.0 ! BRAIN BuChE CONSTANT DBUCE=0.0 ! DIAPHRAGM BuChE CONSTANT HBUCE=0.0 ! LIVER BuChE CONSTANT BLBUCE=0.0 ! Plasma BuChE CONSTANT LUBUCE=0.0 !LUNG BuChE! HEPATIC B-CHOLINE (C) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDHCE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIHCE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRHCE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KAHCE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! HEPATIC B-BUTYRL (B) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDHBE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIHBE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRHBE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KAHBE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! HEPATIC B-CARBOXYL (CR) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDHCR=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIHCR=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRHCR=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KAHCR=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! BRAIN B-CHOLINE (C) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDBCE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIBCE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRBCE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KABCE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! BRAIN B-BUTYRL (B) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDBBE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIBBE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRBBE=0.0 ! HR-1;REACTIVATION OF ESTERASE CONSTANT KABBE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! BRAIN B-CARBOXYL (CR) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDBCR=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIBCR=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRBCR=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KABCR=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! LUNG B-CHOLINE (C) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDLUCE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KILUCE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRLUCE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KALUCE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! LUNG B-BUTYRL (B) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDLUBE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KILUBE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRLUBE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KALUBE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! LUNG B-CARBOXYL (CR) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDLUCR=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KILUCR=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRLUCR=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KALUCR=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! DIAPHRAM B-CHOLINE (C) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDDCE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIDCE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRDCE=0.0 ! HR-1;REACTIVATION OF ESTERASE CONSTANT KADCE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! DIAPHRAM B-BUTYRL (B) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDDBE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIDBE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRDBE=0.0 ! HR-1; REACTIVATION OF ESTERASECONSTANT KADBE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! DIAPHRAM B-CARBOXYL (CR) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDDCR=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIDCR=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRDCR=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KADCR=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! BLOOD/PLASMA B-CHOLINE (C) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDBLCE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIBLCE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRBLCE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KABLCE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! BLOOD/PLASMA B-BUTYRL (B) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDBLBE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIBLBE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRBLBE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KABLBE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! BLOOD/PLASMA B-CARBOXYL (CR) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDBLCR=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIBLCR=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRBLCR=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KABLCR=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! RBC B-CHOLINE (C) ESTERASE RATE CONSTANTS - MODEL 2 CONSTANT KDRBCE=0.0 ! HR-1; DEGRADATION OF ESTERASE CONSTANT KIRBCE=0.0 ! UMOLES-1 L HR-1; INHIBITION OF ESTERASE CONSTANT KRRBCE=0.0 ! HR-1; REACTIVATION OF ESTERASE CONSTANT KARBCE=0.0 ! HR-1; RATE FOR AGING OF ESTERASE

! Enzyme activity (umol/h) ! AChE SBACH=BACHE*VB SDACH=DACHE*VD SHACH=HACHE*VH SBLACH=BLACHE*VBL*(1-HCT) SRBACH=RBCHE*VBL*HCT SLUACH=LUACHE*VLU ! CAE SBRCE=BRCE*VB SDACE=DACE*VD SHECE=HECE*VH SPLOCE=PLOCE*VBL*(1-HCT) SLUECE=LUECE*VLU

! BuChE SBBUC=BBUCE*VB SDBUC=DBUCE*VD SHBUC=HBUCE*VH SBLBUC=BLBUCE*VBL*(1-HCT) SLUBUC=LUBUCE*VLU

! CALCULATION OF ESTERASE BINDING SITES (UMOLES) (MAXWELL, 1987) IBCE=SBACH/TRCE ! TOTAL BRAIN ACHE (UMOLES) IDCE=SDACH/TRCE ! TOTAL DIAPHRAGM ACHE (UMOLES) IHCE=SHACH/TRCE ! TOTAL HEPATIC ACHE (UMOLES) IBLCE=SBLACH/TRCE ! TOTAL PLASMA ACHE (UMOLES) IRBCE=SRBACH/TRCE ! Total RBC AChE (umol) ILUCE=SLUACH/TRCE ! TOTAL LUNG ACHE (UMOLES)

IBBE=SBBUC/TRBE ! TOTAL BRAIN BUCHE (UMOLES) IDBE=SDBUC/TRBE ! TOTAL DIAPHRAGM BUCHE (UMOLES) IHBE=SHBUC/TRBE ! TOTAL HEPATIC BUCHE (UMOLES) IBLBE=SBLBUC/TRBE ! TOTAL PLASMA BUCHE (UMOLES)ILUBE=SLUBUC/TRBE ! TOTAL LUNG BUCHE (UMOLES)

IBCR=SBRCE/TRCR ! TOTAL BRAIN CAE (UMOLES) IDCR=SDACE/TRCR ! TOTAL DIAPHRAGM CAE (UMOLES) IHCR=SHECE/TRCR ! TOTAL HEPATIC CAE (UMOLES) IBLCR=SPLOCE/TRCR ! TOTAL PLASMA CAE (UMOLES) ILUCR=SLUECE/TRCR ! TOTAL LUNG CAE (UMOLES)

! CALCULATION OF ENZ SYN RATE (UMOLE/HR) ! LIVER KSHCE=IHCE*KDHCE ! SYN RATE OF HEPATIC ACHE (UMOLE/HR) KSHBE=IHBE*KDHBE ! SYN RATE OF HEPATIC BCHE (UMOLE/HR) KSHCR=IHCR*KDHCR ! SYN RATE OF HEPATIC BCHE (UMOLE/HR) ! BRAIN KSBCE=IBCE*KDBCE ! SYN RATE OF BRAIN ACHE (UMOLE/HR) KSBBE=IBBE*KDBBE ! SYN RATE OF BRAIN BCHE (UMOLE/HR) KSBCR=IBCR*KDBCR ! SYN RATE OF BRAIN BCHE (UMOLE/HR) ! LUNG KSLUCE=ILUCE*KDLUCE ! SYN RATE OF LUNG ACHE (UMOLE/HR) KSLUBE=ILUBE*KDLUBE ! SYN RATE OF LUNG BCHE (UMOLE/HR) KSLUCR=ILUCR*KDLUCR ! SYN RATE OF LUNG BCHE (UMOLE/HR) ! DIAPHRAGM KSDCE=IDCE*KDDCE ! SYN RATE OF DIAPHRAGM ACHE (UMOLE/HR) KSDBE=IDBE*KDDBE ! SYN RATE OF DIAPHRAGM BCHE (UMOLE/HR) KSDCR=IDCR*KDDCR ! SYN RATE OF DIAPHRAGM BCHE (UMOLE/HR) ! PLASMA KSBLCE=IBLCE*KDBLCE ! SYN RATE OF PLASMA ACHE (UMOLE/HR) KSBLBE=IBLBE*KDBLBE ! SYN RATE OF PLASMA BCHE (UMOLE/HR) KSBLCR=IBLCR*KDBLCR ! SYN RATE OF PLASMA BCHE (UMOLE/HR) ! RBC KSRBCE=KDRBCE*IRBCE ! SYNTHESIS RATE OF RBC (umol/h)

! ACUTE BOLUS ORAL DOSING OF CPF - MODEL 1 CONSTANT ORALC=0.0 ! CPF single oral bolus dose (ug/kg) CONSTANT ORALP=0.0 ! TCPy oral bolus dose (ug/kg) CONSTANT ORALO=0.0 ! CPF-oxon oral bolus dose (ug/kg) CONSTANT KAI=0.0 ! 1ST ORDER ABSORPTION RATE INTESTINE HR-1 CONSTANT KSI=0.0 ! 1ST ORDER TRANSFER STOM TO INTEST HR-1 CONSTANT KAS=0.0 !RAT ONLY, STOM TO LIVER HR-1 CONSTANT KIHP=0.0 ! Transfer of TCPy from sm. intest to compartment 1 (/h) CONSTANT KOS=0.0 ! Transfer of CPF-oxon from sm. intest to liver (/h) CONSTANT KOSI=0.0 !Transfer of CPF-oxon (from an oral dose) to the intestines, note in CPF model for ease CONSTANT FA=0.0 ! FRACTIONAL ABSORPTION FROM GI TRACT

! MOLECULAR WEIGHTS CONSTANT MWC=350.6 ! MW FOR CHLORPYRIFOS - MODEL 1 (G/MOL) CONSTANT MWO=334.5 ! MW FOR CHLORPYRIFOS OXON - MODEL 1 & 2 (G/MOL) CONSTANT MWP=198.4 ! MW FOR TCP - MODEL 1 & 2 (G/MOL)

! Oral Dosing - dose an undefined number of times ! Put times in the array DT (in hours) (absolute time, NOT time since last dose) ! Put the oral dose of chlorpyrifos in the array DORAL (UG/KG)(DORALO FOR OXON) !for dosing AMOUNT instead of /kg (ug) put the oral dose of CPF (AMTCDOSE) OR OXON (AMTODOSE) ! Add one additional dose of zero at a time greater than TSTOP to keep the model running DIMENSION DT(2000), DORAL(2000), DSC(2000), DORALO(2000), AMTCDOSE(2000), AMTODOSE(2000) INTEGER indx indx=1 ! indx is a counter used to track multiple doses SCHEDULE DOSEX .AT. DT(indx) ODOSE=0.0 SCDOSE=0.0 ODOSEO=0.0ADOSEC=0.0 ADOSEO=0.0

! MOLAR CONVERSION & FRACTIONAL ABSORPTION MODIFICATION ODOSEC=ORALC*(BWT/MWC)*FA ! CPF dose conversion (umol) ODOSEP=ORALP*(BWT/MWP)*FA ! TCPy dose coversion (umol) ODOSEO=ORALO*(BWT/MWO)*FA ! CPF-oxon dose conversion (umol)

! Oral infusion AKA FEED CONSTANT FEED=0.0 ! Feed dose (ug/kg) CONSTANT FEEDR=0.0 ! Rate of feed intake, est @ 1.3 day-1 (Saghir 2006) CONSTANT FEEDT=0.0 ! TIME OF FEEDING FEEDOSE=FEED*FEEDR*BWT/24 ! ug/day FEDOSE1=FEEDOSE/MWC ! UMOLES/day - NO FA, ASSUME 100% COMPDOSE=FEEDOSE/BWT*FEEDT ! TOTAL UG/KG DOSED FEEDBALANCE=COMPDOSE*(BWT/MWC) ! CPF dose conversion (umol)

! IV DOSE INFUSION CONSTANT IV=0.0 ! IV DOSE (uG/KG BWT) CONSTANT IVS=0.0 ! IV START TIME (HR) CONSTANT IVE=0.01 ! IV END TIME (HR) IVD=IVE-IVS ! IV INFUSION DURATION (HR) TIV=IV*BWT/MWC ! TOTAL CPF INJECTED (uMOL) IVR=TIV/IVD ! RATE OF CPF DOSE INFUSION (uMOL/HR)

! SUBCUTANEOUS DOSE (JNS) CONSTANT SCDC=0.0 ! SUBQ DOSE (uG/KG BWT) CONSTANT KSC=0.0 ! 1ST ORDER TRANSFER RATE (HR^-1) CONSTANT KSP=0.0 ! 1ST ORDER TRANSFER RATE FROM SUBQ TO PERIPHERAL SUBQ CONSTANT KPS=0.0 ! 1ST ORDER TRANSFER RATE FROM PERIPHERAL SUBQ TO SUBQ DSCDC=((SCDC*BWT)/MWC) ! AMOUNT OF CPF DOSE (uMOL)

!DERMAL DOSE (TSP) CONSTANT DERM=0.0 !UG/KG or ug, depending on which line is used below 549 or 550 CONSTANT SAF=0.0 !FRACTION TOTAL SKIN EXPOSED CONSTANT VLIQ=0.0 !L CONSTANT KPL=0.0 !cm/hr CONSTANT KDIS = 0. ! 1st order dissipation loss from skin to environment, 1/day CONSTANT FAD=0.0 !FRACT DERM ABSORBED, should be 100% available = 1

!REPIRATORY DOSE CONSTANT CONCPPM = 0.0 ! Inhaled conc (ppm) CONSTANT CONCMGM = 0.0 !Inhaled conc (mg/m3) CONSTANT CONCPPMO=0.0 CONSTANT CONCMGMO=0.0 CONSTANT CCON = 0.0 ! For closed chamber CONSTANT CCOFF = 1.0 ! For closed chamber CONSTANT VCHCC = 6400.0 ! Closed chamber volume (mL) VCHA= VCHCC-N*BWT ! ...corrected for animal volume CONSTANT N = 0 ! Number of animals per chamber CONSTANT KLOSS = 0.0 ! Loss from chamber, 1/min CONSTANT DAYSWK = 1.0 ! Number of exposure days per week CONSTANT TMAX = 1440.0 ! Maximum time for exposures CONSTANT FRACIN=0.0 CONSTANT s2=0 !INHALATION ON CONSTANT p2=3 !DERMAL EXPOSURE

CONSTANT D3=5 !5 DAYS/WEEK FOR DERMAL EXPOSURE CONSTANT YEAR=364 !DAYS! TO STOP DERMAL and INHALTION EXPOSURE AT SOME POINT DURING A YEAR (THIS COULD ALSO BE MONTHS...) CONSTANT W2=21 ! DAYS! THIS COMBINES WITH YEAR - 21 HR=3 WEEKS OF EXPOSURE. CONSTANT D3IN=5 !5 DAYS/WEEK FOR inhalation EXPOSURE CONSTANT W2IN=21 ! THIS COMBINES WITH YEAR - 21 WEEKS OF EXPOSURE.- INHALATIONCONSTANT P2IN=3 !INHALATION HR/DAY CONSTANT S2IN=0 !TO OFFSET DSOING START, PROBABLY NEVER SET TO ANYTHING BUT 0 CONSTANT VVOL=0.06 !URNARY OUTPUT, L/HR -Hayes et al, 2015 from NHANES data

! COMPARTMENTAL MODEL FOR TCP ELIMINATION CONSTANT KE=0.0 ! ELIMINATION RATE (HR-1) V1=0.176*BWT^1.01 ! TCPy vol of distribution (L) 0.176*bwt^1.01 - see Smith et al, 2013

! Enzymatic variability CONSTANT VMLv=0.0 CONSTANT VMBLv=0.0 CONSTANT VMHCPv=0.0 CONSTANT VMHHCOv=0.0 CONSTANT VMCBCPv=0.0 CONSTANT VMCBCOv=0.0 CONSTANT VINTTv=0.0 CONSTANT VINTOv=0.0

! lognormal distributions VMLvv=exp(GAUSS(LOG(VMLSTN)-(SQRT(LOG((VMLv)**2.+1))**2.)/2.,SQRT(LOG((VMLv)**2.+1))))-VML STN VMBLvv=((VMLvv+VMLST)/VMLSTN*VMBLSTN+GAUSS(0.,VMBLv))-VMBLSTN VMHCPvv=exp(GAUSS(LOG(VMHCN)-(SQRT(LOG((VMHCPv)**2.+1))**2.)/2.,SQRT(LOG((VMHCPv)**2.+1))) )-VMHCN VMHHCOvv=exp(GAUSS(LOG(VMHHON)-(SQRT(LOG((VMHHCOv)**2.+1))**2.)/2.,SQRT(LOG((VMHHCOv)**2.+ 1))))-VMHHON VMCBCPvv=exp(GAUSS(LOG(VMBCP)-(SQRT(LOG((VMCBCPv)**2.+1))**2.)/2.,SQRT(LOG((VMCBCPv)**2.+1 ))))-VMBCP VMCBCOvv=exp(GAUSS(LOG(VMBCO)-(SQRT(LOG((VMCBCOv)**2.+1))**2.)/2.,SQRT(LOG((VMCBCOv)**2.+1 ))))-VMBCO VINTOvv=exp(GAUSS(LOG(VINTO)-(SQRT(LOG((VINTOv)**2.+1))**2.)/2.,SQRT(LOG((VINTOv)**2.+1))) )-VINTO VINTTvv=exp(GAUSS(LOG(VINTT)-(SQRT(LOG((VINTTv)**2.+1))**2.)/2.,SQRT(LOG((VINTTv)**2.+1))) )-VINTT

!If the Vmax is less than 1% of the nominal, set equal to 1% of nonimal (by setting error to 99% of nominal) VMLvv = RSW(VMLvv+VMLSTN .LT. .01*VMLSTN, -0.99*VMLSTN, VMLvv) VMBLvv = RSW(VMBLvv+VMBLSTN .LT. .1*VMBLSTN, -0.90*VMBLSTN, VMBLvv) !NOTE, VMBLST AND VMHC BOTH DECREASE OVER COURSE OF PREGNANCY - EXTRA "PROTECTION" FROM GOING BELOW ZERO IS NEEDED VMHCPvv = RSW(VMHCPvv+VMHCN .LT. .50*VMHCN, -0.50*VMHCN, VMHCPvv) VMHHCOvv = RSW(VMHHCOvv+VMHHON .LT. .01*VMHHON, -0.99*VMHHON, VMHHCOvv) VMCBCPvv = RSW(VMCBCPvv+VMBCP .LT. .01*VMBCP, -0.99*VMBCP, VMCBCPvv) VMCBCOvv = RSW(VMCBCOvv+VMBCO .LT. .01*VMBCO, -0.99*VMBCO, VMCBCOvv) VINTTvv = RSW(VINTTvv+VINTT .LT. .01*VINTT, -0.99*VINTT, VINTTvv) VINTOvv = RSW(VINTOvv+VINTO .LT. .01*VINTO, -0.99*VINTO, VINTOvv)

! set variable Vmax's VMLSTN=VMLvv+VMLSTN VMBLSTN=VMBLvv+VMBLSTN VMHCN=VMHCPvv+VMHCN VMHHON=VMHHCOvv+VMHHON VMBCP=VMCBCPvv+VMBCP VMBCO=VMCBCOvv+VMBCO VINTT=VINTTvv+VINTT VINTO=VINTOvv+VINTO

!other variability based on point (LOCAL) senstivity analyses CONSTANT KDRBCEv=0.0 CONSTANT KIRBCEv=0.0 CONSTANT HCTv=0.0 CONSTANT TRCRv=0.0CONSTANT HECEv=0.0 CONSTANT KRHCRv=0.0 CONSTANT KSIv=0.0 CONSTANT KRRBCEv=0.0 ! lognormal distributions KDRBCEvv=exp(GAUSS(LOG(KDRBCE)-(SQRT(LOG((KDRBCEv)**2.+1))**2.)/2.,SQRT(LOG((KDRBCEv)**2.+ 1))))-KDRBCE KIRBCEvv=exp(GAUSS(LOG(KIRBCE)-(SQRT(LOG((KIRBCEv)**2.+1))**2.)/2.,SQRT(LOG((KIRBCEv)**2.+ 1))))-KIRBCE KRRBCEvv=exp(GAUSS(LOG(KRRBCE)-(SQRT(LOG((KRRBCEv)**2.+1))**2.)/2.,SQRT(LOG((KRRBCEv)**2.+ 1))))-KRRBCE HCTvv=exp(GAUSS(LOG(HCTN)-(SQRT(LOG((HCTv)**2.+1))**2.)/2.,SQRT(LOG((HCTv)**2.+1))))-HCTN TRCRvv=exp(GAUSS(LOG(TRCR)-(SQRT(LOG((TRCRv)**2.+1))**2.)/2.,SQRT(LOG((TRCRv)**2.+1))))-TR CR KRHCRvv=exp(GAUSS(LOG(KRHCR)-(SQRT(LOG((KRHCRv)**2.+1))**2.)/2.,SQRT(LOG((KRHCRv)**2.+1))) )-KRHCR HECEvv=exp(GAUSS(LOG(HECE)-(SQRT(LOG((HECEv)**2.+1))**2.)/2.,SQRT(LOG((HECEv)**2.+1))))-HE CE KSIvv=exp(GAUSS(LOG(KSI)-(SQRT(LOG((KSIv)**2.+1))**2.)/2.,SQRT(LOG((KSIv)**2.+1))))-KSI !IF value goes below 1%, set to 1% of nominal mean KDRBCEvv = RSW(KDRBCEvv+KDRBCE .LT. .01*KDRBCE, -0.99*KDRBCE, KDRBCEvv) KIRBCEvv = RSW(KIRBCEvv+KIRBCE .LT. .01*KIRBCE, -0.99*KIRBCE, KIRBCEvv) KRRBCEvv = RSW(KRRBCEvv+KRRBCE .LT. .01*KRRBCE, -0.99*KRRBCE, KRRBCEvv) HCTvv=RSW(HCTvv+HCTN .LT. .01*HCT, -0.99*HCTN, HCTvv) TRCRvv = RSW(TRCRvv+TRCR .LT. .01*TRCR, -0.99*TRCR, TRCRvv) KRHCRvv = RSW(KRHCRvv+KRHCR .LT. .01*KRHCR, -0.99*KRHCR, KRHCRvv) HECEvv = RSW(HECEvv+HECE .LT. .01*HECE, -0.99*HECE, HECEvv) KSIvv = RSW(KSIvv+KSI .LT. .01*KSI, -0.99*KSI, KSIvv) ! set variable params KDRBCE=KDRBCEvv+KDRBCE KIRBCE=KIRBCEvv+KIRBCE KRRBCE=KRRBCEvv+KRRBCE HCTN=HCTvv+HCTN TRCR=TRCRvv+TRCR HECE=HECEvv+HECE KSI=KSIvv+KSI KOSI=KSIvv+KOSI KRHCR=KRHCRvv+KRHCR

! Blood flow to each compartment (L/h) QF=(QFC+QFCv)*VF QH=(QHC+QHCVv)*VH QR=(QRC+QRCv)*VR QS=QSC*VS+QSCv QB=QBC*VB QD=QDC*VD QC=QF+QH+QR+QS+QB+QD+QPLA ! Total flow

! TIMING COMMANDS CONSTANT TSTOP=1 ! STOP SIMULATION (HR)

END ! END OF INITIAL

!###################################################################### DYNAMIC

!GROWING PREG COMPARTMENTS

IF(PREG.EQ.0)THEN PAFC=0 ELSE PAFC=0.1 END IF

IF(PREG.EQ.1)THENVUTR=(80+8.2931*GWEEK+0.3546*GWEEK^2)/1000 !Abduljalil et al 2012 ELSE VUTR=1E-99 END IF

IF (PREG.EQ.1)THEN VFI=VFN+((0.1305*GWEEK)+(0.0008*GWEEK^2)) !Abduljalil et al 2012 ELSE VFI=0 END IF IF (PREG.EQ.1)THEN VFINIT=((VFN+0.1305*GWEEKSTART+0.0008*GWEEKSTART^2)) ELSE VFINIT=0 END IF

IF (PREG.EQ.1)THEN VBLI=VBLN-0.003741*GWEEK+0.004375*GWEEK^2-8.748e-5*GWEEK^3!+0.0098*GWEEK !Abduljalil et al 2012 ELSE VBLI=0 END IF IF (PREG.EQ.1)THEN VBLINIT=VBLN-0.003741*GWEEKSTART+0.004375*GWEEKSTART^2-8.748e-5*GWEEKSTART^3!+0.0098*GWEEK ELSE VBLINIT=0 END IF

IF (PREG.EQ.1)THEN VSI=VSN-0.2313*GWEEK+0.02311*GWEEK^2-0.0003376*GWEEK^3 !Abduljalil et al 2012 - 2/3 OF FFM ELSE VSI=0 END IF IF (PREG.EQ.1)THEN VSINIT=VSN-0.2313*GWEEKSTART+0.02311*GWEEKSTART^2-0.0003376*GWEEKSTART^3 ELSE VSINIT=0 END IF

IF (PREG.EQ.1)THEN VRI=VRN+0.004209*GWEEK+0.002854*GWEEK^2-7.610E-5*GWEEK^3!!+((80+8.2931*GWEEK+0.3546*GWEEK^ 2)/1000)!FIT TO TOTAL FFM - 1/3 - UTIRUS ELSE VRI=0 END IF IF (PREG.EQ.1)THEN VRINIT=VRN+0.004209*GWEEKSTART+0.002854*GWEEKSTART^2-7.610E-5*GWEEKSTART^3 ELSE VRINIT=0 END IF

IF (PREG.EQ.0)THEN PFC=PFCN ELSE PFC=PFCN-1.3*GWEEK-0.1249*GWEEK^2+0.00273*GWEEK^3 END IF

IF (PREG.EQ.0)THEN PFO=PFON ELSE PFO=PFON-0.365*GWEEK-0.039*GWEEK^2+0.000849*GWEEK^3 END IFIF (PREG.EQ.0)THEN HCT=HCTN ELSE HCT=HCTN-((0.0544*GWEEK+0.0021*GWEEK^2)/100) END IF

IF (PREG.EQ.0)THEN VMHHO=VMHHON ELSE VMHHO=VMHHON+0.68*GWEEK+0.18*GWEEK^2 END IF

IF (PREG.EQ.0)THEN VMHC=VMHCN ELSE VMHC=VMHCN-2.29*GWEEK-0.279*GWEEK^2 END IF

IF (PREG.EQ.0)THEN VMLST=VMLSTN !20% LOSS OVER PREGNANCY - CONSERVATIVE, Weitman et al found no hepatic difference in Peroxinase activity in liver ELSE VMLST=VMLSTN-346*GWEEK+0.9703*GWEEK^2 END IF VMBLN=VMBL1/(1+exp((VMBL2-AGE)/VMBL3)) ! Blood Vmaxc CPF-oxon -> TCPy (umol/hr/L plasma), Dynamic: logistic func MOVED FOR PREG COMMENT THIS OUT FOR BOOTSTRAP IF (PREG.EQ.1)THEN VMBLST=VMBLSTN-1945*GWEEK+35.04*GWEEK^2!+3.12*GWEEK^3 ELSE VMBLST=VMBLSTN END IF !VMBLST=VMBL*VBL*(1-HCT) ! Blood CPF-oxon -> TCPy

! Age IF (SPECIES .EQ. 0) THEN AGE=AGE0+TIME/24.0 ! Rat age (D) ELSE AGE=AGE0+TIME/8766 ! Human age (Y) END IF

! Age dependent B4 & B8 for humans (Luecke 2007) IF ((AGE .GE. AGE1) .AND. (AGE .LT. AGE2) .AND. (SPECIES .EQ. 1)) THEN B4x=B4;B8x=0 ELSE IF ((AGE .GE. AGE3) .AND. (SPECIES .EQ. 1)) THEN B4x=0;B8x=B8 ELSE B4x=0;B8x=0 END IF

! BWT (kg) Gompertz (Luecke 2007) IF (AGE .GE. AGE2) THEN BWTINIT=B5*EXP((B6/B7)*(1-EXP(-B7*(AGE-AGE2))))+B8x*(AGE-AGE3) ELSE BWTINIT=B1*EXP((B2/B3)*(1-EXP(-B3*AGE)))+B4x*(AGE-AGE1) END IF BWT=(BWTINIT*(1.-BWSW)+VFET+VPLA+VUTR+(VFI-VFINIT)+(VBLI-VBLINIT)+(VSI-VSINIT)+(VRI-VRINIT ))+BWST*BWSW

BWTG=BWTINIT*1000 ! BWT kg to grams for compartment vol calcs

IF (SPECIES .EQ. 0) THEN LBWT=LOG(BWTINIT) ! Log of BWT for rat brain calc ELSE LBWT=BWTINIT*1000END IF

IF (PREG.EQ.0)THEN VF=VFN ELSE VF=VFI END IF

IF (PREG.EQ.0)THEN VBL=VBLN ELSE VBL=VBLI END IF

IF (PREG.EQ.0)THEN VS=VSN ELSE VS=VSI END IF

IF (PREG.EQ.0)THEN VR=VRN ELSE VR=VRI END IF

TSA=71.81*(BWT**0.425)*(HT**0.725) !DUBOIS AND DUBOIS 1916 HUMAN SA - MOVED TO INCLUDE INCREASE DURING PREGNANCY SA=SAF*TSA

IF (PREG.EQ.0)THEN QR=(QRC+QRCv)*VR ELSE QR=((QRC+0.006)+QRCv)*VR END IF

IF (PREG.EQ.0) THEN VFET=1e-99 ELSE VFET = 3.55 * (EXP(-16.081*EXP(-5.67E-4*GTIME))+ EXP(-140.178*EXP(-7.01E-4*GTIME))) !VFET = 0.01*EXP(13.6*(1-EXP(-0.0702*GWEEK))) END IF

IF (PREG.EQ.0) THEN VPLA=1e-99 ELSE !VPLA = 0.85*EXP(-9.434*EXP(-5.23E-4*GTIME)) VPLA = (1e-19+0.00675*GWEEK+0.000258*GWEEK^2) END IF

! Human Blood flow to placenta (L/hr) IF (PREG.EQ.0) THEN QPLA=0 ELSE QPla = 58.5 * VPla END IF

IF (PREG.EQ.0) THEN QUTR=0 ELSE QUTR = 62 * VPla END IF! Scaled permeability-area product

PAF = PAFC * (VFet**0.75)

! Compartment volumes (frac of BWT) VBC=VB0+(VB1*LBWT)+(VB2*LBWT**2)+(VB3*LBWT**3)+(VB4*LBWT**4)+(VB5*LBWT**5)+(VB6*LBWT**6) ! Brain VHC=VH0+(VH1*BWTG)+(VH2*BWTG**2)+(VH3*BWTG**3)+(VH4*BWTG**4) ! Liver VBLC=VBL0+(VBL1*BWTG)+(VBL2*BWTG**2) ! Blood VFC=VF0+(VF1*BWTG)+(VF2*BWTG**2)+(VF3*BWTG**3)+(VF4*BWTG**4)+(VF5*LBWT**5)+(VF6*LBWT**6) ! Fat VAC=VA0+(VA1*BWTG)+(VA2*BWTG**2)+(VA3*BWTG**3)+(VA4*BWTG**4)+(VA5*BWTG**5)+(VA6*BWTG**6) ! Adipose VKC=VK0+(VK1*BWTG)+(VK2*BWTG**2) ! Kidney (in rapid) VSPC=VSP0+(VSP1*BWTG)+(VSP2*BWTG**2) ! Spleen (in rapid) VLC=VL0+(VL1*BWTG)+(VL2*BWTG**2) ! Lung VGIC=VGI0+(VGI1*BWTG)+(VGI2*BWTG**2)+(VGI3*BWTG**3) ! Intestines (in rapid) VMC=VM0+(VM1*BWTG)+(VM2*BWTG**2)+(VM3*BWTG**3)+(VM4*BWTG**4) ! Muscle (in slow) VSKC=VSK0+(VSK1*BWTG)+(VSK2*BWTG**2)+(VSK3*BWTG**3)+(VSK4*BWTG**4)+(VSK5*BWTG**5) ! Skin (in slow) VFC=VFC+VFCv

VRC=VKC+VSPC+VLC+VGIC

VSC=VMC+VSKC+VBMC+(VAC-VFC) ! Slow

VSC=VSC+VSCu VRC=VRC+VRCu VBC=VBC+VBCu VHC=VHC+VHCu VFC=VFC+VFCu VBLC=VBLC+VBLCu VDC=VDC+VDCu VINTC=VINTC+VINTCu

! Compartment volumes (L) VB=VBC*BWT VH=VHC*BWT !VBL=VBLC*BWT !VF=VFC*BWT VRN=VRC*BWTINIT !VS=VSC*BWT VD=VDC*BWT VINT=VINTC*BWT VLU=VLC*BWT !LUNG added 5.13

! Blood flow to each compartment (L/h) QF=(QFC+QFCv)*VF QH=(QHC+QHCVv)*VH QR=(QRC+QRCv)*VR QS=QSC*VS+QSCv QB=QBC*VB QD=QDC*VD QC=QF+QH+QR+QS+QB+QD+QPLA ! Total flow

!mucociliator FRLUGI=1-FRACIN !FRACTIONAL transfer of CPF to GI tract - per O'Flaherty Chromium model FRLUGIO=1-FRACIN !FRACTIONAL transfer of OXON to GI tract RLUGIO=FRLUGIO*CIO*QALV

! Age dependent metabolism (comment out for bootstrap) !VMBL=VMBL1/(1+EXP((VMBL2-AGE)/VMBL3)) ! Blood Vmaxc CPF-oxon -> TCPy (umol/hr/L plasma), dynamic logistic

! Scaling Vmaxc to Vmax (umol/h)VINTO=VINTOC*VINT ! Sm int. CPF -> CPF-oxon VINTT=VINTTC*VINT ! Sm int. CPF -> TCPy VINTOX=VINTOXC*VINT ! Sm int. CPF-oxon -> TCPy VMBCO=VMCBCO*VB ! Brain CPF -> CPF-oxon VMBCP=VMCBCP*VB ! Brain CPF -> TCPy VMBCPT=VMBCPTC*VB VMAXOLU=VMAXOLUC*VLU ! LUNG CPF->OXON VMAXTLU=VMAXTLUC*VLU ! LUNG CPF->TCP VMAXPLU=VMAXPLUC*VLU !LUNG OXON->TCP

! Enzyme activity (umol/h) ! AChE SBACH=BACHE*VB SDACH=DACHE*VD SHACH=HACHE*VH SLUACH=LUACHE*VLU SBLACH=BLACHE*VBL*(1-HCT) SRBACH=RBCHE*VBL*HCT ! CAE SBRCE=BRCE*VB SDACE=DACE*VD SHECE=HECE*VH SLUECE=LUECE*VLU SPLOCE=PLOCE*VBL*(1-HCT) ! BuChE SBBUC=BBUCE*VB SDBUC=DBUCE*VD SHBUC=HBUCE*VH SHBUC=HBUCE*VH SBLBUC=BLBUCE*VBL*(1-HCT)

! CALCULATION OF ESTERASE BINDING SITES (UMOLES) (MAXWELL, 1987) IBCE=SBACH/TRCE ! TOTAL BRAIN ACHE (UMOLES) IDCE=SDACH/TRCE ! TOTAL DIAPHRAGM ACHE (UMOLES) IHCE=SHACH/TRCE ! TOTAL HEPATIC ACHE (UMOLES) IBLCE=SBLACH/TRCE ! TOTAL PLASMA ACHE (UMOLES) ILUCE=SLUACH/TRCE IRBCE=SRBACH/TRCE ! Tot RBC AchE (umol)

IBBE=SBBUC/TRBE ! TOTAL BRAIN BUCHE (UMOLES) IDBE=SDBUC/TRBE ! TOTAL DIAPHRAGM BUCHE (UMOLES) IHBE=SHBUC/TRBE ! TOTAL HEPATIC BUCHE (UMOLES) ILUBE=SLUBUC/TRBE IBLBE=SBLBUC/TRBE ! TOTAL PLASMA BUCHE (UMOLES)

IBCR=SBRCE/TRCR ! TOTAL BRAIN CAE (UMOLES) IDCR=SDACE/TRCR ! TOTAL DIAPHRAGM CAE (UMOLES) IHCR=SHECE/TRCR ! TOTAL HEPATIC CAE (UMOLES) ILUCR=SLUECE/TRCR IBLCR=SPLOCE/TRCR ! TOTAL PLASMA CAE (UMOLES)

! CALCULATION OF ENZ SYN RATE (UMOLE/HR) ! LIVER KSHCE=IHCE*KDHCE ! SYN RATE OF HEPATIC ACHE (UMOLE/HR) KSHBE=IHBE*KDHBE ! SYN RATE OF HEPATIC BCHE (UMOLE/HR) KSHCR=IHCR*KDHCR ! SYN RATE OF HEPATIC BCHE (UMOLE/HR) ! LUNG KSLUCE=ILUCE*KDLUCE ! SYN RATE OF LUNG ACHE (UMOLE/HR) KSLUBE=ILUBE*KDLUBE ! SYN RATE OF LUNG BCHE (UMOLE/HR) KSLUCR=ILUCR*KDLUCR ! SYN RATE OF LUNG BCHE (UMOLE/HR) ! BRAIN KSBCE=IBCE*KDBCE ! SYN RATE OF BRAIN ACHE (UMOLE/HR) KSBBE=IBBE*KDBBE ! SYN RATE OF BRAIN BCHE (UMOLE/HR)KSBCR=IBCR*KDBCR ! SYN RATE OF BRAIN BCHE (UMOLE/HR) ! DIAPHRAGM KSDCE=IDCE*KDDCE ! SYN RATE OF DIAPHRAGM ACHE (UMOLE/HR) KSDBE=IDBE*KDDBE ! SYN RATE OF DIAPHRAGM BCHE (UMOLE/HR) KSDCR=IDCR*KDDCR ! SYN RATE OF DIAPHRAGM BCHE (UMOLE/HR) ! PLASMA KSBLCE=IBLCE*KDBLCE ! SYN RATE OF PLASMA ACHE (UMOLE/HR) KSBLBE=IBLBE*KDBLBE ! SYN RATE OF PLASMA BCHE (UMOLE/HR) KSBLCR=IBLCR*KDBLCR ! SYN RATE OF PLASMA BCHE (UMOLE/HR) ! RBC KSRBCE=KDRBCE*IRBCE ! Synthesis rate of RBC (umol/hr)

! Variable enzymology VMBCP=VMCBCPvv+VMBCP VMBCO=VMCBCOvv+VMBCO VINTT=VINTTvv+VINTT VINTO=VINTOvv+VINTO

DISCRETE DOSEX ! Oral dose code ODOSE=ODOSE+DORAL(indx)*(BWT/MWC)*FA ! CPF dose molar conversion SCDOSE=SCDOSE+DSC(indx)*(BWT/MWC) ! SC dose ODOSEO=ODOSEO+DORALO(indx)*(BWT/MWO)*FA !OXON DOSE MOLAR CONVERSION ADOSEO=ADOSEO+AMTODOSE(indx)*FA/MWC ADOSEC=ADOSEC+AMTCDOSE(indx)*FA/MWO indx=indx+1 SCHEDULE DOSEX .AT. DT(indx) END

! Exposure Conditions Based on User Defined Initial Amounts of Chemical (mg) IF (concppm.EQ.0.0) THEN concmg=concmgm/1000 !CONvERT MG/M3 to mg/L ELSE CONCmg = CONCppm/24451. !Convert ppm to mg/Liter! ENDIF

CONSTANT DOSEINTERVAL=24 !TIME BETWEEN DAILY DOSES

! Exposure Conditions Based on User Defined Initial Amounts of Chemical (mg) IF (concppmO.EQ.0.0) THEN concmgO=concmgmO/1000 !CONvERT MG/M3 to mg/L ELSE CONCmgO = CONCppmO/24451. !Convert ppm to mg/Liter! ENDIF

! Scaled Pulmonary Ventilation Rate CONSTANT QPC=0 !(L/hr) FOR 1 KG ANIMAL (Gentry et al) QALV= (QPC * (BWT**0.74))*0.7 ALGORITHM IALG=2 TERMT(TIME .GE. TSTOP) ! STATEMENT TO STOP EXECUTION

!NOTE THE FOLLOWING CODE ADDED 4/24/14 - AFTER THE PUBLISHED MANUSCRIPT. iT DOES NOT AFFECT MODEL OUTPUT TO DATE. VOLUME=0.654+(AGE*0.0663)+(AGE^2*-0.000664) !this is for water dosing only, for use by EPA to dose over time. Water consumption changes with age, this is fit to 90% !data from EPA exposures factors handbook (2011), table 3-7 using Graphpad Prism CONSTANT EVENTS=1 !TIMES/DAY TO DRINK DRINKING=VOLUME/EVENTS !NOTE THIS IS FOR A DRINKING WATER SCENARIO ONLY, DATA IS INPUT USING A EXCEL TABLE AND THE NUMBER OF TIMES/DAY THAT A PERSON DRINKS IS USED TO ESTIMATE DOSE FROM WATER

!###################################################################### DERIVATIVE!for pregnancy model - tsp 2.15 Days = (TIME / 24.0) + GDstart

IF (PREG .EQ. 1) THEN Gtime = TIME + GDstart*24.0 !time of gestation (hr) ELSE GTIME=0 END IF GWEEK = GTIME/168 GWEEKSTART=GDSTART/7

! IV DOSE/INFUSION IF ((TIME .LE. IVE) .AND. (TIME .GE. IVS)) THEN IVDOSE=IVR ELSE IVDOSE=0.0 END IF

! Inhalation Exposures !pulse instructions !FOR BOTH INALAITON AND DERMAL, A PULSE IS USED TO TURN ON/OFF EXPOSURES HOURLY, DAILY, AND OR YEARLY ! THE FIRST (0,YEAR,W2IN) IS THE LONG-TERM ON/OFF - THE UNITS ARE days!!! SO, YEAR=365 WILL TURN OFF THE OVERALL EXPOSURE AFTER 1 YEAR - NO MORE PULSES WILL OCCUR AND NO MORE DOSING ! THE SECOND IS FOR WEEKELY CONTROL. AGAIN, UNITS ARE DAYS. D3IN (D3) WILL SET HOW MANY DAYS/WEEK DOSING OCCURS. 1-7 WILL WORK. ! the final (pulse(s2IN,24,p2IN)) is how many hours/day - 1-24 can be set. Note, if 24 is set, then dosing will be continuous until d3(in) turns it off. CIM = CONCMG*DUMMYIN DUMMYIN=pulse(0,YEAR*24,W2IN*24)*pulse(0,7*24,d3IN*24)*(pulse(s2IN,24,p2IN)) CI=CIM/MWC*1000 !DOSE IN UMOL

!Dermal pulse - DUMMY = pulse(0,YEAR*24,W2*24)*pulse(0,7*24,d3*24)*(pulse(s2,24,p2)) !this is a change from the published model, 2015 !original published multi-route model: pulse(0,7*24,d3*24)*(pulse(s2,24,p2))

! CENTRAL SC COMPARTMENT RASC=(KPS*APSC)-(KSC*ASC)-(KSP*ASC) ! CHANGE IN SC COMPARTMENT (uMOL/HR) ASC=INTEG(RASC,DSCDC)+SCDOSE ! AMT IN SC COMPARTMENT (uMOL) RASCA=KSC*ASC ! RATE OF ABSORPTION (uMOL/HR)

! PERIPHERAL SC COMPARTMENT (PSC) RAPSC=(KSP*ASC)-(KPS*APSC) ! CHANGE IN PSC COMPARTMENT (uMOL/HR) APSC=INTEG(RAPSC,0.0) ! AMT IN PSC COMPARTMENT (uMOL)

! FEED DOSE ! SWITCHES FOR FEED OFF/ON IF ((TIME .LE. FEEDT)) THEN FEEDDOSE=FEDOSE1 ELSE FEEDDOSE=0.0 END IF

! DERMAL ABSORPTION FROM SKIN !!! ADDED CJH 20JUL2015... ! Rate of change of amount on skin now has three terms: ! 1. Depletion from absorption into skin, via KPL! 2. Depletion from dissipative loss, via KDISS (1/day) ! 3. Accumulation from daily exposure, via DERM (mg/kg/day) ! ! Compute rate at which CPF is being deposited on skin ! DDOSE is amt deposited each 24 hours, so convert to a 1/h rate - THIS IS NOT 24 HR, IT IS DOSE DEPOSITED/time of exposure/day(TSP) VMDERMO=VMCDERMCO*VSKCC ! DERMAL CPF -> CPF-oxon VMDERMC=VMCDERMCP*VSKCC ! DERMAL CPF -> TCPy VMDERMEST=VMDERMESTC*VSKCC ! DERMAL ESTERASE OXON -> TCPy

DDOSE=((DERM*BWT)/MWC)*FAD !total amount uMol use when dose is ug/kg/day ASURF=INTEG(RASURF,DDOSE)

CSURF=ASURF/VLIQ

RASURF=-((((KPL*SA/1000)*CSURF))*DUMMY) - (KDIS/24.0)*ASURF

RADL=((((KPL*SA/1000)*CSURF))*DUMMY)-RADLL-RMETDT-RMETDO

ADL=INTEG(RADL,0.0)

RADLL=ADL*PSKL !RATE OF ABSORPTION ADLT=INTEG(RADLL,0.0) !TOT ABSORBED

CADERM=ADL/VSKCC

RMETDT=CADERM*VMDERMC/(KMDERMCP+CADERM)!METAB TO TCPY RMETDO=CADERM*VMDERMO/(KMDERMCO+CADERM)!METAB TO OXON ADLO=INTEG(RMETDO,0.0)

RDERMTOTOX=RMETDO-(PSKO*ADERMOXTOT)-RDERMOX ! Rate of CPF-oxon change in skin ADERMOXTOT=INTEG(RDERMTOTOX,0.0) ! Amt of CPF-oxon in skin RDERMTO=PSKO*ADERMOXTOT ! Rate of CPF-oxon transfer to blood ADLTO=INTEG(RDERMTO,0.0) ! TOTAL OXON ABSORBED CADLO=ADERMOXTOT/VSKCC ! Conc of CPF-oxon in skin ADERMCO=INTEG(RDERMTO,0.0)

RDERMOX=CADLO*VMDERMEST/(KMDERMEST+CADLO)

ADLTCPYC=INTEG(RMETDT,0.0) ADLTCPYO=INTEG(RMETDO,0.0) TOTDERMTCPY=ADLTCPYC+ADLTCPYO

!###################################################################### ! Stomach RSTOM=FEEDDOSE-KSI*ASTOM-KAS*ASTOM+AMUC*KMUC !NOTE RLUGI IS FROM LUNG "ELEVATOR", STRUCTURE BASED ON O'Flaherty Chromium model ASTOM=ODOSE+ADOSEC+ODOSEC+INTEG(RSTOM,0.0) ! Amt of CPF in stomach RSTOML=KAS*ASTOM ASTOML=INTEG(RSTOML,0.0) RSTOMO=-KOSI*ASTOMO ASTOMO=ODOSEO+ADOSEO+INTEG(RSTOMO,0.0)

RLUGI=FRLUGI*CI*QALV-AMUC*KMUC AMUC=INTEG(RLUGI,0.0)

! Intestine RINTC=(KSI*ASTOM)-MINTO-MINTTC-(KAI*AINTC) ! Rate of CPF change in intestine (umol/h) AINTC=INTEG(RINTC,0.0) ! Amt of CPF in intestine (umol) RAO=KAI*AINTC ! Rate of CPF transfer to liver CINTC=AINTC/VINT ! Conc of CPF in intestine (umol/L) MINTO=VINTO*CINTC/(KMINTO+CINTC) ! Metab CPF to CPF-oxon MINTTC=VINTT*CINTC/(KMINTC+CINTC) ! Metab CPF to TCPy

RINTO=MINTO-(KOS*AINTO)-MINTOX+(KOSI*ASTOMO) ! Rate of CPF-oxon change in intestineAINTO=INTEG(RINTO,0.0) ! Amt of CPF-oxon in intestine w/ CPF-oxon oral dose RLIVO=AINTO*KOS ! Rate of CPF-oxon transfer to liver CINTO=AINTO/VINT ! Conc of CPF-oxon in intestine MINTOX=VINTOX*CINTO/(KMINTOX+CINTO) ! Metab CPF-oxon to TCPy (PON1)

RINTP=MINTTC+MINTOX-RAP ! Rate of TCPy change in intestine AINTP=ODOSEP+INTEG(RINTP,0.0) ! Amt of TCPy in intestine w/ TCPy oral dose CINTP=AINTP/VINT ! Conc of TCPy in intestine RAP=KIHP*AINTP ! Rate of TCPy transfer from intestine to liver

!#######################################################################

! MODEL 1 CPF

! LIVER (C) - MODEL 1 RAH=QH*(CAF-CVHF)-RHCO-RHCP+RAO+RSTOML ! RATE OF CHANGE IN LIVER AH=INTEG(RAH,0.0) ! AMT CPF IN LIVER CH=AH/VH ! CONC CPF IN LIVER CVHF=CH/PHC ! FREE CPF IN BLD LEAVING LIVER HAUC=INTEG(CH,0.0) ! AUC CPF IN LIVER RHCO=VMHHO*CH/(KMHHCO+CH) ! Rate of CPF -> CPF-oxon AMOX=INTEG(RHCO,0.0) !AMOUNT METABOLIZED TO OXON - UMOL RHCP=VMHC*CH/(KMHCP+CH) ! Rate of CPF -> TCPy AMTCP=INTEG(RHCP,0.0) !AMOUNT METABOLIZED TO TCPY - UMOL

RALINH = QALV * FRACIN * CI*N !RATE INTO LUNG RALU=QC*(CAF-CLU)-(QALV*CLEX) - RAMLUOX-RAMLUT + RALINH! RATE OF CHANGE IN LUNG ALU=INTEG(RALU,0.0) ! AMT CPF IN LUNG CLU=ALU/VLU ! CONC CPF IN LUNG CVLU=CLU/PLU ! FREE CONC CPF IN BLOOD LEAVING LUNG FAULU=INTEG(CLU,0.0) ! AUC CPF IN LUNG ALUINH=INTEG(RALINH,0.0)!UMOL ABSORBED TALUINH=ALUINH INMG=ALUINH*MWC/BWT/1000 !MG/KG ABSORBED

AMLUGI=INTEG(RLUGI,0.0) RMUCOS=AMLUGI*KMUC ALUNGDOSE=INTEG(RMUCOS,0.0)

! AMOUNT EXHALED CLEX = CVLU / PLAIR ! CONCENTRATION, UMOL/L RAEX = QALV * CLEX AEX = INTEG(RAEX, 0.0) ! AMOUNT, MG PER AEXC = AEX * N ! AMOUNT, MG, FOR A GROUP OF RATS

!----------LUNG METABOLISM---- RAMLUOX = VMAXOLU*CLU/(KMOLU+CLU)!rate to oxon AMLUOX = INTEG(RAMLUOX, 0.0) CLUOX=AMLUOX/PLUO RAMLUT = VMAXTLU*CLU/(KMTLU+CLU) !rate to tcpy AMLUOT=INTEG(RAMLUT,0.0)

! FAT (C) - MODEL 1 RAF=QF*(CAF-CVFF) ! RATE OF CHANGE IN FAT AF=INTEG(RAF,0.0) ! AMT CPF IN FAT CF=AF/VF ! CONC CPF IN FAT CVFF=CF/PFC ! FREE CONC CPF IN BLOOD LEAVING FAT FAUC=INTEG(CF,0.0) ! AUC CPF IN FAT

! SLOWLY PERF (C) - MODEL 1 RAS=QS*(CAF-CVSF) ! RATE OF CHANGE IN SLOW PERFAS=INTEG(RAS,0.0) ! AMT CPF IN SLOW PERF CS=AS/VS ! CONC CPF IN SLOW PERF CVSF=CS/PSC ! FREE CPF IN BLOOD LEAVING SLOW PERF

! DIAPHRAM (C)- MODEL 1 RAD=QD*(CAF-CVDF)-RDPCO-RDPCP ! RATE OF CHANGE IN DIAPHRAM AD=INTEG(RAD,0.0) ! AMT CPF IN DIAPHRAM CD=AD/VD ! CONC CPF IN DIAPHRAM CVDF=CD/PDC ! FREE CONC CPF IN BLOOD LEAVING DIAPHRAM RDPCO=VMCDPO*CD/(KMDPCO+CD) ! Rate of CPF -> CPF-oxon RDPCP=VMCDPP*CD/(KMDPCP+CD) ! Rate of CPF -> TCPy ADCO=INTEG(RDPCO, 0.0)

! RAPID PERF (C) - MODEL 1 RAR=QR*(CAF-CVRF) ! RATE OF CHANGE IN RAPID PERF AR=INTEG(RAR,0.0) ! AMT CPF IN RAPID PERF CR=AR/VR ! CONC CPF IN RAPID PERF CVRF=CR/PRC ! FREE CPF IN BLOOD LEAVING RAPID PERF

! BRAIN (C) RAB=QB*(CAF-CVBF)-RBCO-RBCP ! RATE OF CHANGE IN BRAIN AB=INTEG(RAB,0.0) ! AMT CPF IN BRAIN CB=AB/VB ! CONC CPF IN BRAIN CVBF=CB/PBC ! FREE CONC CPF IN BLOOD LEAVING BRAIN RBCO=VMBCO*CB/(KMBCO+CB) ! Rate of CPF -> CPF-oxon RBCP=VMBCP*CB/(KMBCP+CB) ! Rate of CPF -> TCPy

! Amount in Fetus (mg) RAFet = PAF * (CPla - CFet) AFet = INTEG(RAFet, 0.0) CFet = AFet / VFet CFETPG=CFET*350.6*1000 AUCCFet = INTEG(CFet, 0.0) ! Amount in Placenta (mg) RAPla = (QPla * (CAF - CVPla)) + (PAF * (CFET - CPLA)) !NOTE, ONE WAY TO GET MORE TANSFER WOULD BE TO USE TOTAL, NOT BOUND (CA INSTEAD OF CAF), BUT NEED TO DESCRIBE CORRECTLY APla = INTEG(RAPla, 0.0) CPla = APla / VPla CVPla = CPla / PPla CVPLAPM=CVPla*350.6*1000

! BLOOD VENOUS & ARTERIAL (C) - MODEL 1 RABL=QC*(CV-CA)+RASCA+IVDOSE+RADLL ! RATE OF CHANGE IN MIXED BLOOD RLBLD=QC*(CLU-CAF) !LUNG BLOOD ALBLD=INTEG(RLBLD,0.0) ABL=INTEG(RABL,0.0)+INTEG(RLBLD,0.0) ! AMOUNT CPF IN MIXED BLOOD CBL=ABL/VBL ! CONC CPF IN MIXED BLOOD CBLB=CBL*FBC ! CONC CPF BOUND IN MIXED BLOOD CBLF=CBL*(1-FBC) ! CONC FREE CPF IN ARTERIAL BLOOD CV=CVEF+CBLB ! TOTAL CPF IN VENOUS BLOOD CVPM=CV*350.6*1000 ! TOTAL FREE CPF VENOUS BLOOD FROM TISSUES CVEF=(QH*CVHF+QF*CVFF+QS*CVSF+QR*CVRF+QB*CVBF+QD*CVDF+CVPLA*QPLA)/QC CA=CBL/PBL ! CONC CPF IN ARTERIAL BLOOD CAPM=CA*350.6*1000 !conc cpf in arterial blood units of pg/ml CAF=CA*FUBC !(1-FBC) ! CONC FREE CPF IN ARTERIAL BLOOD BLAUC=INTEG(CBL,0.0) ! AUC CPF IN BLOOD CAAUC=INTEG(CA,0.0) BLAUCPM=INTEG(CAPM,0.0) BLAUCAVG=BLAUC/TSTOP!####################################################################### ! MODEL 2 CPF-OXON

! LIVER (O) - MODEL 2 RAHO=RHCO+QH*(CAOF-CVHOF)-HAE-(RHPCE+RHPBE+RHPCR)+RLIVO ! RATE OF CHANGE IN LIVER AHO=INTEG(RAHO,0.0) ! AMT O IN LIVER CHO=AHO/VH ! CONC O IN LIVER CVHOF=CHO/PHO ! O IN BLD LEAVING LIVER HAUCO=INTEG(CHO,0.0) ! AUC OXON IN LIVER

! HEPATIC A-ESTERASE ACTIVITY HAE=VMLST*CHO/(KMLST+CHO) ! FORMATION OF TCP FROM OXON AMPONH=INTEG(HAE,0.0) !CLEARANCE OF OXN IN LIVER - UMOL RHTCP=(RHPCE+RHPBE+RHPCR)+HAE+RHCP ! RATE OF TCP IN LIVER AHTCP=INTEG(RHTCP,0.0) ! AMT TCP IN LIVER CHTCP=AHTCP/VH ! CONC TCP IN LIVER HAUCCP=INTEG(CHTCP,0.0) ! AUC TCP IN LIVER

! HEPATIC B-ESTERASE ACTIVITY HBE=AHCE+AHBE+AHCR ! TOTAL B-ESTERASE (UMOLES) = CHOLINE + BUTYRYL + CARBOXYL IHE=100*(HBE/(ANHCE+ANHBE+ANHCR)) ! % TOTAL B-ESTERASE INHIBITION HCE=100*(AHCE/ANHCE) ! % CHOLINE-ESTERASE INHIBITION HBES=100*(AHBE/ANHBE) ! % BUTURYL-ESTERSE INHIBITION HCR=100*(AHCR/ANHCR) ! % CARBOXYL-ESTERASE INHIBITION

! CHOLINE ESTERASE ACTIVITY RHCE=KSHCE-AHCE*(KDHCE+KIHCE*CHO)+HOCE*KRHCE ! RATE OF CHE ESTERASE AHCE=INTEG(RHCE,IHCE) ! LIVER CHE ESTERASE (UMOLES) RNHCE=KSHCE-ANHCE*KDHCE ! Rate of naive ChE ANHCE=INTEG(RNHCE,IHCE) ! Amt of naive ChE RHOCE=AHCE*KIHCE*CHO-HOCE*(KAHCE+KRHCE) ! RATE OF CHE INHIBITION HOCE=INTEG(RHOCE,0.0) ! LIVER CHE INHIBITED (UMOLES) RHPCE=AHCE*KIHCE*CHO ! RATE OF TCP FORMATION

! BUTYRYL ESTERASE ACTIVITY RHBE=KSHBE-AHBE*(KDHBE+KIHBE*CHO)+HOBE*KRHBE ! RATE OF BE ESTERASE ACT AHBE=INTEG(RHBE,IHBE) ! LIVER BE ESTERASE ACT (UMOLES) RNHBE=KSHBE-ANHBE*KDHBE ! Rate of naive BE act ANHBE=INTEG(RNHBE,IHBE) ! Amt of naive BE RHOBE=AHBE*KIHBE*CHO-HOBE*(KAHBE+KRHBE) ! RATE OF BE INHIBITION HOBE=INTEG(RHOBE,0.0) ! LIVER BE INHIBITED (UMOLES) RHPBE=AHBE*KIHBE*CHO ! RATE OF TCP FORMATION

! CARBOXYL ESTERASE ACTIVITY RHCR=KSHCR-AHCR*(KDHCR+KIHCR*CHO)+HOCR*KRHCR ! RATE OF CR ESTERASE ACT AHCR=INTEG(RHCR,IHCR) ! LIVER CR ESTERASE ACT (UMOLES) RNHCR=KSHCR-ANHCR*KDHCR ! Rate of naive CR ANHCR=INTEG(RNHCR,IHCR) ! Amt of naive CR RHOCR=AHCR*KIHCR*CHO-HOCR*(KAHCR+KRHCR) ! RATE OF CR INHIBITION HOCR=INTEG(RHOCR,0.0) ! LIVER CR INHIBITED (UMOLES) RHPCR=AHCR*KIHCR*CHO ! RATE OF TCP FORMATION

!LUNG CIMO = concmgO* pulse(0,7*24,5*24)*(pulse(s2,24,p2)) ! for a 5 day/wk exposure, change first pulse to pulse(0,7*24,5*24) ! for daily, pulse(0,1e6,24) CIO=CIMO/MWO RALINHO = QALV * FRACIN * CIO*N !RATE INTO LUNG RALUO=RAMLUOX+QALV*(CAOF-CVLUO) - LAE- (QALV*CLEX)+ RALINHO-(RLUPCE+RLUPBE+RLUPCR)! RATE OF CHANGE IN LUNG ALUO=INTEG(RALUO,0.0) ! AMT CPF IN LUNG CLUO=ALUO/VLU ! CONC CPF IN LUNG CVLUO=CLUO/PLU ! FREE CONC CPF IN BLOOD LEAVING LUNG FAULUO=INTEG(CLUO,0.0) ! AUC CPF IN LUNG ALUINHO=INTEG(RALINHO,0.0)TALUINHO=ALUINHO

! AMOUNT EXHALED CLEXO = CVLUO / PLAIRO ! CONCENTRATION, MG/L RAEXO = QALV * CLEXO AEXO = INTEG(RAEXO, 0.0) ! AMOUNT, MG PER AEXCO = AEXO * N ! AMOUNT, MG, FOR A GROUP OF RATS

! PULMONARY A-ESTERASE ACTIVITY LAE=VMAXPLU*CLUO/(KMPLUC+CLUO) ! FORMATION OF TCP FROM OXON RLUTCP=(RLUPCE+RLUPBE+RLUPCR)+LAE+RAMLUT ! RATE OF TCP IN LUNG ALUTCP=INTEG(RLUTCP,0.0) ! AMT TCP IN LUNG CLUTCP=ALUTCP/VLU ! CONC TCP IN LUNG LUAUCCP=INTEG(CLUTCP,0.0) ! AUC TCP IN LUNG

! PULMONARY B-ESTERASE ACTIVITY LUBE=ALUCE+ALUBE+ALUCR ! TOTAL B-ESTERASE (UMOLES) = CHOLINE + BUTYRYL + CARBOXYL ILUE=100*(LUBE/(ANLUCE+ANLUBE+ANLUCR)) ! % TOTAL B-ESTERASE INHIBITION LUCE=100*(ALUCE/ANLUCE) ! % CHOLINE-ESTERASE INHIBITION LUBES=100*(ALUBE/ANLUBE) ! % BUTURYL-ESTERSE INHIBITION LUCR=100*(ALUCR/ANLUCR) ! % CARBOXYL-ESTERASE INHIBITION

! CHOLINE ESTERASE ACTIVITY RLUCE=KSLUCE-ALUCE*(KDLUCE+KILUCE*CLUO)+LUOCE*KRLUCE ! RATE OF CHE ESTERASE ALUCE=INTEG(RLUCE,ILUCE) ! LUNG CHE ESTERASE (UMOLES) RNLUCE=KSLUCE-ANLUCE*KDLUCE ! Rate of naive ChE ANLUCE=INTEG(RNLUCE,ILUCE) ! Amt of naive ChE RLUOCE=ALUCE*KILUCE*CLUO-LUOCE*(KALUCE+KRLUCE) ! RATE OF CHE INHIBITION LUOCE=INTEG(RLUOCE,0.0) ! LUNG CHE INHIBITED (UMOLES) RLUPCE=ALUCE*KILUCE*CLUO ! RATE OF TCP FORMATION

! BUTYRYL ESTERASE ACTIVITY RLUBE=KSLUBE-ALUBE*(KDLUBE+KILUBE*CLUO)+LUOBE*KRLUBE ! RATE OF BE ESTERASE ACT ALUBE=INTEG(RLUBE,ILUBE) ! LUNG BE ESTERASE ACT (UMOLES) RNLUBE=KSLUBE-ANLUBE*KDLUBE ! Rate of naive BE act ANLUBE=INTEG(RNLUBE,ILUBE) ! Amt of naive BE RLUOBE=ALUBE*KILUBE*CLUO-LUOBE*(KALUBE+KRLUBE) ! RATE OF BE INHIBITION LUOBE=INTEG(RLUOBE,0.0) ! LUNG BE INHIBITED (UMOLES) RLUPBE=ALUBE*KILUBE*CLUO ! RATE OF TCP FORMATION

! CARBOXYL ESTERASE ACTIVITY RLUCR=KSLUCR-ALUCR*(KDLUCR+KILUCR*CLUO)+LUOCR*KRLUCR ! RATE OF CR ESTERASE ACT ALUCR=INTEG(RLUCR,ILUCR) ! LUNG CR ESTERASE ACT (UMOLES) RNLUCR=KSLUCR-ANLUCR*KDLUCR ! Rate of naive CR ANLUCR=INTEG(RNLUCR,ILUCR) ! Amt of naive CR RLUOCR=ALUCR*KILUCR*CLUO-LUOCR*(KALUCR+KRLUCR) ! RATE OF CR INHIBITION LUOCR=INTEG(RLUOCR,0.0) ! LUNG CR INHIBITED (UMOLES) RLUPCR=ALUCR*KILUCR*CLUO ! RATE OF TCP FORMATION

! BRAIN OXON (O)- MODEL 2 RABO=QB*(CAOF-CVBOF)-(RBPCE+RBPBE+RBPCR)+RBCO-RBCOP ! RATE OF CHANGE IN BRAIN ABO=INTEG(RABO,0.0) ! AMT O IN BRAIN CBO=ABO/VB ! CONC O IN BRAIN CVBOF=CBO/PBO ! CONC O IN BLD LEAVING BRAIN BAUCO=INTEG(CBO,0.0) ! AUC O IN BRAIN RBCOP=VMBCPT*CBO/(KMBCPT+CBO) ! Rate of CPF -> CPF-oxon

! BRAIN B-ESTERASE ACTIVITY BBE=ABCE+ABBE+ABCR ! TOTAL B-ESTERASE = CHOLINE + BUTYRYL + CARBOXYL IBE=100*(BBE/(ANBCE+ANBBE+ANBCR)) ! % TOTAL B-ESTERASE INHIBITION BCE=100*(ABCE/ANBCE) ! % CHOLINE-ESTERASE INHIBITION BCEPERC=100-BCE !PERCENT INHIBITED RATHER THAN INHIBITION BBES=100*(ABBE/ANBBE) ! % BUTURYL-ESTERSE INHIBITION BCR=100*(ABCR/ANBCR) ! % CARBOXYL-ESTERASE INHIBITION! CHOLINE ESTERASE ACTIVITY RBCE=KSBCE-ABCE*(KDBCE+KIBCE*CBO)+BOCE*KRBCE ! RATE OF CHE ESTERASE ACT ABCE=INTEG(RBCE,IBCE) ! BRAIN CHE ESTERASE ACT (UMOLES) RNBCE=KSBCE-ANBCE*KDBCE ! Rate of naive ChE act ANBCE=INTEG(RNBCE,IBCE) ! Amt of naive ChE RBOCE=ABCE*KIBCE*CBO-BOCE*(KABCE+KRBCE) ! RATE OF CHE INHIBITION BOCE=INTEG(RBOCE,0.0) ! BRAIN CHE INHIBITED (UMOLES) RBPCE=ABCE*KIBCE*CBO ! RATE OF TCP FORMATION

! BUTYRYL ESTERASE ACTIVITY RBBE=KSBBE-ABBE*(KDBBE+KIBBE*CBO)+BOBE*KRBBE ! RATE OF BE ESTERASE ACT ABBE=INTEG(RBBE,IBBE) ! BRAIN BE ESTERASE ACT (UMOLES) RNBBE=KSBBE-ANBBE*KDBBE ! Rate of naive BE act ANBBE=INTEG(RNBBE,IBBE) ! Amt of naive BE RBOBE=ABBE*KIBBE*CBO-BOBE*(KABBE+KRBBE) ! RATE OF BE INHIBITION BOBE=INTEG(RBOBE,0.0) ! BRAIN BE INHIBITED (UMOLES) RBPBE=ABBE*KIBBE*CBO ! RATE OF TCP FORMATION

! CARBOXYL ESTERASE ACTIVITY RBCR=KSBCR-ABCR*(KDBCR+KIBCR*CBO)+BOCR*KRBCR ! RATE OF CR ESTERASE ACT ABCR=INTEG(RBCR,IBCR) ! BRAIN CR ESTERASE ACT (UMOLES) RNBCR=KSBCR-ANBCR*KDBCR ! Rate of naive CRE act ANBCR=INTEG(RNBCR,IBCR) ! Amt of naive CRE RBOCR=ABCR*KIBCR*CBO-BOCR*(KABCR+KRBCR) ! RATE OF CR INHIBITION BOCR=INTEG(RBOCR,0.0) ! BRAIN CR INHIBITED (UM L-1) RBPCR=ABCR*KIBCR*CBO ! RATE OF TCP FORMATION

! DIAPHRAM OXON (O)- MODEL 2 RADO=QD*(CAOF-CVDOF)-(RDPCE+RDPBE+RDPCR)+RDPCO ! RATE OF CHANGE IN DIAPHRAM ADO=INTEG(RADO, 0.0) ! AMT O IN DIAPHRAM CDO=ADO/VD ! CONC O IN DIAPHRAM CVDOF=CDO/PDO ! O IN BLD LEAVING DIAPHRAM DAUCO=INTEG(CDO,0.0) ! AUC O IN DIAPHRAM

! DIAPHRAM B-ESTERASE ACTIVITY DBE=ADCE+ADBE+ADCR ! TOTAL B-ESTERASE = CHOLINE + BUTYRYL + CARBOXYL DBE1=ADCE+ADBE ! TOTAL CHOLINE + BUTURYL IDE=100*(DBE/(ANDCE+ANDBE+ANDCR)) ! % TOTAL B-ESTERASE INHIBITION IDE1=100*(DBE1/(ANDCE+ANDBE)) ! % TOTAL CHOLINE + BUTYRYL INHIBITION DCE=100*(ADCE/ANDCE) ! % CHOLINE-ESTERASE INHIBITION DBES=100*(ADBE/ANDBE) ! % BUTURYL-ESTERSE INHIBITION DCR=100*(ADCR/ANDCR) ! % CARBOXYL-ESTERASE INHIBITION

! AChE ACTIVITY RDCE=KSDCE-ADCE*(KDDCE+KIDCE*CDO)+DOCE*KRDCE ! RATE OF CHE ESTERASE ACT ADCE=INTEG(RDCE,IDCE) ! DIAPHRAGM CHE ESTERASE ACT (UMOLES) RNDCE=KSDCE-ANDCE*KDDCE ! Rate of naive ChE act ANDCE=INTEG(RNDCE,IDCE) ! Amt of naive ChE RDOCE=ADCE*KIDCE*CDO-DOCE*(KADCE+KRDCE) ! RATE OF CHE INHIBITION DOCE=INTEG(RDOCE,0.0) ! DIAPHRAGM CHE INHIBITED (UMOLES) RDPCE=ADCE*KIDCE*CDO ! RATE OF TCP FORMATION

! BUTYRYL ESTERASE ACTIVITY RDBE=KSDBE-ADBE*(KDDBE+KIDBE*CDO)+DOBE*KRDBE ! RATE OF BE ESTERASE ACT ADBE=INTEG(RDBE,IDBE) ! DIAPHRAGM BE ESTERASE ACT (UMOLES) RNDBE=KSDBE-ANDBE*KDDBE ! Rate of naive BE act ANDBE=INTEG(RNDBE,IDBE) ! Amt of naive BE RDOBE=ADBE*KIDBE*CDO-DOBE*(KADBE+KRDBE) ! RATE OF BE INHIBITION DOBE=INTEG(RDOBE,0.0) ! DIAPHRAGM BE INHIBITED (UMOLES) RDPBE=ADBE*KIDBE*CDO ! RATE OF TCP FORMATION

! CARBOXYL ESTERASE ACTIVITY RDCR=KSDCR-ADCR*(KDDCR+KIDCR*CDO)+DOCR*KRDCR ! RATE OF CR ESTERASE ACT ADCR=INTEG(RDCR,IDCR) ! DIAPHRAGM CR ESTERASE ACT (UMOLES)RNDCR=KSDCR-ANDCR*KDDCR ! Rate of naive CR ANDCR=INTEG(RNDCR,IDCR) ! Amt of naive CR RDOCR=ADCR*KIDCR*CDO-DOCR*(KADCR+KRDCR) ! RATE OF CR INHIBITION DOCR=INTEG(RDOCR,0.0) ! DIAPHRAGM CR INHIBITED (UMOLES) RDPCR=ADCR*KIDCR*CDO ! RATE OF TCP FORMATION

! FAT (O) - MODEL 2 RAFO=QF*(CAOF-CVFOF) ! RATE OF CHANGE IN FAT AFO=INTEG(RAFO,0.0) ! AMT O IN FAT CFO=AFO/VF ! CONC O IN FAT CVFOF=CFO/PFO ! FREE O IN BLD LEAVING FAT FAUCO=INTEG(CFO,0.0) ! AUC O IN FAT

! AMOUNT IN FETUS (MG) RAFETO = PAF * (CPLAO - CFETO) !note PAF for oxon = for CPF, estimated AFETO = INTEG(RAFETO, 0.0) CFETO = AFETO / VFET AUCCFETO = INTEG(CFETO, 0.0) ! AMOUNT IN PLACENTA (MG) RAPLAO = (QPLA * (CAOF - CVPLAO)) + (PAF * (CFETO- CPLAO)) APLAO = INTEG(RAPLAO, 0.0) CPLAO = APLAO / VPLA CVPLAO = CPLAO/ PPLAO

! SLOWLY PERF (O) - MODEL 2 RASO=QS*(CAOF-CVSOF) ! RATE OF CHANGE IN SLOW PERF ASO=INTEG(RASO,0.0) ! AMT O IN SLOW PERF CSO=ASO/VS ! CONC O IN SLOW PERF CVSOF=CSO/PSO ! O IN BLD LEAVING SLOW PERF SAUCO=INTEG(CSO,0.0) ! AUC O IN SLOW PERF

! RAPID PERF (O) - MODEL 2 RARO=QR*(CAOF-CVROF) ! RATE OF CHANGE IN RAPID PERF ARO=INTEG(RARO,0.0) ! AMT OXON IN RAPID PERF CRO=ARO/VR ! CONC OXON IN RAPID PERF CVROF=CRO/PRO ! FREE OXON IN BLD LEAVING RAPID PERF RAUCO=INTEG(CRO,0.0) ! AUC OXON IN RAPID PERF

! BLOOD (O) - MODEL 2 RABLO=QC*(CVO+CVLUO-CAO)-RBLOP+RDERMTO ! RATE OF CHANGE IN MIXED BLOOD COMPT ABLO=INTEG(RABLO,0.0)!+INTEG(RLBLDO,0.0) ! AMT O IN MIXED BLOOD COMPT CBLO=ABLO/VBL ! CONC O IN MIXED BLOOD COMPT CAO=CBLO/PBLO ! CONC O IN ARTERIAL BLOOD CAOF=ABLO*(1-FBO)/VBL ! CONC OF FREE O IN ARTERIAL BLOOD CAOB=ABLO*(FBO)/VBL ! Conc CPF-oxon bound in art. blood (umol/L) BLAUCO=INTEG(CBLO,0.0) ! AUC O IN VENOUS BLOOD BLAUCOF=INTEG(CAOF,0.0) RBLOPA=VMBLST*CAOF/(KMBLST+CAOF) ! A-esterase CPF-oxon -> TCPy AMPONBL=INTEG(RBLOPA,0.0) !AMOUNT OXON CLEARED BY PLASMA PON1 RBLOPB=RBLPBE+RBLPCR+RBLPCE+RRBPCE ! Total B-esterase CPF-oxon -> TCPy RBLOP=RBLOPA+RBLOPB ! Total CPF-oxon -> TCPy CVO=(QH*CVHOF+QF*CVFOF+QS*CVSOF+QR*CVROF+QB*CVBOF+QD*CVDOF+CVPLAO*QPLA)/QC+CAOB ! CONC CPF-oxon VENOUS BLOOD NMCVO=CVO*1000 !IN nM TO PLACE ON OUTPUT SCALE

! BLOOD/PLASMA B-ESTERASE ACTIVITY BLBE=ABLCE+ABLBE+ABLCR ! TOTAL B-ESTERASE = AChE + BuChE + CaE BLBE1=ABLCE+ABLBE ! TOTAL AChE + BuChE IBLE=100*(BLBE/(ANBLCE+ANBLBE+ANBLCR)) ! % Total B-esterase inhibition in plasma IBLE1=100*(BLBE1/(ANBLCE+ANBLBE)) ! % Total AChE + BuChE inhibition in plasma IBLE1PERC=100-IBLE1 !PERCENT INHIBITED RATHER THAN INHIBITION BLCE=100*(ABLCE/ANBLCE) ! % AChE inhibition in plasma BLBES=100*(ABLBE/ANBLBE) ! % BuChE inhibition in plasmaBLCR=100*(ABLCR/ANBLCR) ! % CaE inhibition in plasma RBCCE=100*(ARBCE/ANRBCE) ! % AChE inhibition in RBC RBCPERC=100-RBCCE !CALCULATE % INHIBITED INSTEAD OF INHIBITION RBCAVG=INTEG(RBCPERC,0.0)/TSTOP !AVG ACTIVITY (NOT INHIBITION) TBLCE=100*((ABLCE+ARBCE)/(ANBLCE+ANRBCE)) ! % AChE inhibition in blood

! Plasma AChE Activity RBLCE=KSBLCE-ABLCE*(KDBLCE+KIBLCE*CBLO)+BLOCE*KRBLCE ! RATE OF CHE ESTERASE ACT ABLCE=INTEG(RBLCE,IBLCE) ! VENOUS CHE ESTERASE ACT (UMOLES) RNBLCE=KSBLCE-ANBLCE*KDBLCE ! Rate of venous naive ChE ANBLCE=INTEG(RNBLCE,IBLCE) ! Amt of venous naive ChE RBLOCE=ABLCE*KIBLCE*CBLO-BLOCE*(KABLCE+KRBLCE) ! RATE OF CHE INHIBITION BLOCE=INTEG(RBLOCE,0.0) ! VENOUS CHE INHIBITED (UMOLES) RBLPCE=ABLCE*KIBLCE*CBLO ! RATE OF TCP FORMATION

! Plasma BuChE Activity RBLBE=KSBLBE-ABLBE*(KDBLBE+KIBLBE*CBLO)+BLOBE*KRBLBE ! RATE OF BE ESTERASE ACT ABLBE=INTEG(RBLBE,IBLBE) ! VENOUS BE ESTERASE ACT (UMOLES) RNBLBE=KSBLBE-ANBLBE*KDBLBE ! Rate of venous naive BE ANBLBE=INTEG(RNBLBE,IBLBE) ! Amt of venous naive BE RBLOBE=ABLBE*KIBLBE*CBLO-BLOBE*(KABLBE+KRBLBE) ! RATE OF BE INHIBITION BLOBE=INTEG(RBLOBE,0.0) ! VENOUS BE INHIBITED (UMOLES) RBLPBE=ABLBE*KIBLBE*CBLO ! RATE OF TCP FORMATION

! Plasma CaE Activity RBLCR=KSBLCR-ABLCR*(KDBLCR+KIBLCR*CBLO)+BLOCR*KRBLCR ! RATE OF CR ESTERASE ACT ABLCR=INTEG(RBLCR,IBLCR) ! VENOUS CR ESTERASE ACT (UMOLES) RNBLCR=KSBLCR-ANBLCR*KDBLCR ! Rate of venous naive CR ANBLCR=INTEG(RNBLCR,IBLCR) ! Amt of venous naive CR RBLOCR=ABLCR*KIBLCR*CBLO-BLOCR*(KABLCR+KRBLCR) ! RATE OF CR INHIBITION BLOCR=INTEG(RBLOCR,0.0) ! VENOUS CR INHIBITED (UMOLES) RBLPCR=ABLCR*KIBLCR*CBLO ! RATE OF TCP FORMATION

! RBC AChE Activity RRBCCE=KSRBCE-ARBCE*(KDRBCE+KIRBCE*CBLO)+RBCOCE*KRRBCE ! RATE OF RBC CHE ESTERASE ACT ARBCE=INTEG(RRBCCE,IRBCE) ! VENOUS RBC CHE ESTERASE ACT (UMOLES) RNRBCCE=KSRBCE-ANRBCE*KDRBCE ! Rate of RBC naive ChE ANRBCE=INTEG(RNRBCCE,IRBCE) ! Amt of RBC naive ChE RRBOCE=ARBCE*KIRBCE*CBLO-RBCOCE*(KARBCE+KRRBCE) ! RATE OF CHE INHIBITION RBCOCE=INTEG(RRBOCE,0.0) ! VENOUS CHE INHIBITED (UMOLES) RRBPCE=ARBCE*KIRBCE*CBLO ! RATE OF TCP FORMATION

! TOTAL AUC FOR OXON IN ALL COMPARTMENTS TAUCO=HAUCO+BAUCO+DAUCO+SAUCO+RAUCO+FAUCO+BLAUCO

!####################################################################### ! TCPy ! TOTAL RATE OF TCP FORMATION RP=RHCP+HAE+RHPCE+RHPBE+RHPCR+RBPCE+RBPBE+RBPCR+RDPCE+RDPBE+RDPCR+RBLOP+RAP+RBCP+RLUTCP+RB COP+RDPCP+RMETDT ATCP=INTEG(RP,0.0) ! TCP (UMOLES) RA1=RP-RAE ! Rate of change in TCPy compartment 1 (umol/h) A1=INTEG(RA1,0.0) ! Amt of TCPy in compartment 1 (umol) CBLP=A1/V1 ! TCPy conc in compartment 1 (umol/L) RAE=A1*KE ! Rate of TCPy excretion (umol/h) AE=INTEG(RAE,0.0) ! Amt of TCPy excreted (umol) AEUG=AE*198.4 urinetcpy = RAE*198.4/VVOL !conc in (ug/L), C.Tan urinetumol=RAE/VVOL !!conc in (umol/L), assuming urine flow rate = 2.4 L/h C. Tan !Blanker et al, 2001 = 1.5 L/day = 0.06 L/hr !Hays et al., 2015 - 0.7 ml/hr/kg = 0.05 L/hr - LOW 0.02, HIGH 0.4

END ! END OF DERIVATIVE!####################################################################### ! Total mass of CPF, CPF-oxon, and TCPy (umol) TMASSC=ASTOM+AINTC+AH+AF+AS+AD+AR+AB+ABL+ASC+APSC+ALU+APLA+AFET ! CPF TMASSO=AINTO+AHO+AFO+ASO+ADO+ARO+ABO+ABLO+ALUO+ADLO+APLAO ! CPF-oxon TMASSP=AINTP+A1+AE ! TCPy TMASS=TMASSC+TMASSO+TMASSP ! Total mass ! Mass BalanceTDOSE=ODOSE+ODOSEC+ADOSEC+ADOSEO+ODOSEP+ODOSEO+SCDOSE+TIV+DSCDC+ADLT+ALUINH+ALUNGDOSE-AEXAEXO+FEEDBALANCE TDOSEUG=TDOSE*MWC MASSBAL=TDOSE/(TMASS+1E-9) ! Should ~1 !Tissue volume checks VTOTCOMPARTMENTS=(VHC+VFC+VSC+VRC+VDC+VBC+VBLC+VLC)/0.9 !should ~0.9-1.1 BWTotal=(0.9*BWT)-(VH+VF+VS+VD+VR+VB+VBL+VPLA+VUTR) !should <10 for a human

END ! END OF DYNAMIC

END ! END OF PROGRAM