% Gender neutral or male specific values, except for female BTW and fat available % Set sex=1 to access female parameters

SPECIES=1; SEX=0; PREG=0; PAFC=0; PAFO=0; GDSTART=0; BWST=70;

% Gompertz BWT Parameters (Luecke 2007) B1=3.42826;B2=2.188189;B3=1.506303;B5=34.35453;B6=0.179781;B7=0.221175; B4=2.462428;B8=-0.0911; AGE0=30; AGE1=2.949004;AGE2=11;AGE3=21.66022;

if(SEX==1) % set Female BWT Parameters B1=3.4;B2=2.07402;B3=1.504154;B5=34.8806;B6=0.2120837;B7=0.443786; B4=2.672665;B8=0.31127; AGE1=2.949004;AGE2=11;AGE3=21.86533; end

% Dynamic organ volumes % VBC Parameters (Refit Valentine 2002 & Young 2009) VB6=0;VB5=0;VB4=5.132e-22;VB3=-2.463e-16;VB2=4.354e-11; VB1=-3.465e-6;VB0=1.216e-1; % VHC (Refit Valentine 2002 & Young 2009) VH4=1.701E-22;VH3=-7.393E-17;VH2=1.082E-11;VH1=-6.789E-7;VH0=3.917E-2; % VBL (Young 2009) VBL2=6.54E-13;VBL1=-3.50E-7;VBL0=8.97E-2; % VFC (Refit, JNS w/ Valentin 2002 & Lafortuna 2005) VF6=-2.036e-30;VF5=1.203e-24;VF4=-2.718e-19;VF3=2.892e-14;VF2=-1.422e-09; VF1=2.803e-05;VF0=3.484e-02; if(SEX==1) % set Female VFC VF6=-1.273e-30;VF5=7.249e-25;VF4=-1.558e-19;VF3=1.540e-14;VF2=-6.787e-10; VF1=1.401e-05;VF0=9.217e-02; end % VAC (Fit, JNS w/ Valentin 2002 & Lafortuna 2005 fat/.8) VA6=-2.353e-30;VA5=1.387e-24;VA4=-3.116e-19;VA3=3.268e-14;VA2=-1.542e-9;VA1=2.617e-05; VA0=2.044e-01; % VLC (Young 2009) VL2=0;VL1=-4.55e-8;VL0=1.86e-2; % VKC (Young 2009) VK2=3.33e-13;VK1=-6.69e-8;VK0=7.26e-3; % VSPC (Young 2009) VSP2=0;VSP1=-5.57e-9;VSP0=3.12e-3; % VGIC (Brown 1997, sum of stom and both intestines) VGI3=0;VGI2=0;VGI1=0;VGI0=0.0165; % VMC (Refit, JNS w/ Valentin 2002 & Janssen 2000) VM4=-5.061e-21;VM3=2.052e-15;VM2=-2.865e-10;VM1=1.436e-5;VM0=1.268e-1; % VSKC (Young 2009) VSK5=-1.1e-27;VSK4=8.62e-22;VSK3=-2.58e-16;VSK2=3.68e-11; VSK1=-2.56e-6;VSK0=1.03e-1;

% Constant organ volumes VBMC=0.021; % Brown 1997 (red only, yellow is in adipose) VDC=0.0003; VPC=0.00148; % Young 2009, Brown 1997 VINTC=0.0091; % Just small intestine (Brown 1997) VFETC=0,VPLAC=0,VFI=0,VFINIT=0;% Clear doses DT(200), DORAL(200), DSC(200), DORALO(200), AMTCDOSE(200), AMTODOSE(200); DT=ones(size(DT))*1E6; % Sets all oral dose times to a long time DORAL=zeros(size(DORAL)); % Sets all oral dose amounts to zero DSC=zeros(size(DSC)); % Sets all SC dose amounts to zero DORALO=zeros(size(DORALO)); AMTODOSE=zeros(size(AMTODOSE)); % Sets all oral dose amounts to zero AMTCDOSE=zeros(size(AMTCDOSE)); % Sets all oral dose amounts to zero CONCPPM=0.0; CONCMGM=0.0; CONCMG=0.0; N=1; VCHA=5e10; DERM=0.0; ORALC=0.0; ORALO=0.0; ORALP=0.0; CONCL=0.0; DERM=0; IV=0.0; % IV dose (ug/kg) IVS=0.0; % IV start time (h) IVE=0.1; % IV end time (h) SCDC=0.0; % SC dose FEED=0.0; % Feed dose (ug/kg feed) FEEDR=0.0; % Feed rate (kg/h) FEEDT=0.0; % Feed time SLORAL=0.0; % Repeated oral gavage dose SA=100; % Surface area exposed dermally (SQ CM) VLIQ=1.0; % Volume of dose applied to skin (L) %TSA=20466; % Total surface area (SQ CM), human value! TCHNG=5e55; % Time to stop dermal exposure %TSTOP=1

% Transfer Rates KAS=0.; % CPF stomach -> liver this is for rat only, set to 0 for human KSI=0.31; % CPF stomach -> intestine, optimized with Nolan 1984 CBLP and AE KAI=3.1; % CPF intestine -> liver, optimized with Nolan 1984 CBLP and AE KIHP=8.7; % TCPy intestine -> liver KOS=2; % CPF-oxon intestine -> liver KOSI=1.5; %CPF-oxon from an oral dose ->intestine (OPTIMIZED IN RATS) KSC=0.0; % Central SC compart -> blood KSP=0.0; % Central SC -> peripheral SC KPS=0.0; % Peripheral SC -> central SC KPL=5.5e-5; %optimized against Nolan data FA=1; % Fractional oral Absorption FAD=1; %FRACTIONAL DERMAL ABSORPTION

% Small intestine metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM) VINTTC= 53; %parallogram approach from measured in rat liver->Intestine(Poet et al., 2003)to human KMINTC=21; % - scaling hepatic by protein content gives 53*0.39=21 VINTOC=28 ; %parallogram approach from measured in rat liver->Intestine(Poet et al., 2003)to human KMINTO=33.2; % scaling hepatic by protein content = 85*0.39=33.2 VINTOXC=82 ; %parallogram approach from measured in rat liver->Intestine(Poet et al., 2003)to human KMINTOX=192; % scaling hepatic by protein content 492*0.39=192

% Hepatic metabolic constants, Vmaxc (umol/hr/g tissue), Km (uM) VMHCP=1.36e3; % CPF -> TCP, median from Smith 2010 B KMHCP=21; % Smith 2010 median; 53- scaling hepatic by protein content gives 53*0.39=21 VMHHCO=6.30E2; % CPF -> CFP-oxon, Smith 2010 median KMHHCO=33.2; % Smith 2010 median; 85 scaling hepatic by protein content = 85*0.39=33.2VML=1.29e+05; % CPF-oxon -> TCP, Smith 2010B median KMLST=192; % Smith 2010 median; 491.8 - scaling hepatic by protein content 492*0.39=192

% Plasma metabolic constants, Vmaxc (umol/hr/L plasma), Km (uM) VMBL1=432000;VMBL2=3.052;VMBL3=3.900; % CPF-oxon -> TCP, logistic fit to Smith 2010 B KMBLST=192.0; % Smith 2010 B: 192.0 med, 203.2 mean

% Brain metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM) VMCBCO=12.6; % CPF -> CPF-oxon, 0.149 Extrap from Chambers 1989, 0.91 Extrap from Layshock 2009 unpub, estimated at 2% hepatic KMBCO=33.2; % Same as liver VMCBCP=27.2; % CPF -> TCPy, Extrap from Layshock 2009 unpub KMBCP=21; % Same as liver KMBCPT=192; %Brain oxon ->TCPy VMBCPTC=1.94e4; %Brain oxon ->TCPy

%lung KMOLU=33.2; %liver KMTLU=21 ; VMAXTLUC=1.36e3; % LUNG CPF->TCP VMAXOLUC=6.3e2; % LUNG CPF->OXON VMAXPLUC=27.2 ; %2% of liver KMPLUC= 192; KMUC=0.02; %OPTIMIZED IN RATS (FROM Hotchkiss inhalation report) FRACIN=0.046; %MPPD MODEL PREDICTed REACHING DEEP LUNG (0.233 for the mid dose per J. Hotchkiss), 20% of that optimize

% diaphragm metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM)copied from brain VMCDPCO=12.6; % CPF -> CPF-oxon, 2% OF HEPATIC KMDPCO=33.2; % Same as intestine VMCDPCP=27.2; % CPF -> CPF-oxon, 2% OF HEPATIC KMDPCP=21; % Same as intestine

%DERMAL VMCDERMCO=12.6; % CPF -> CPF-oxon, 2% OF HEPATIC KMDERMCO=33.2; % same as hepatic VMCDERMCP=27.2; % CPF -> CPF-oxon, 2% OF HEPATIC. Extrap from Layshock 2009 unpub KMDERMCP=21; % Same as hepatic KMDERMEST=19; % Km CPF-oxon -> TCPy (umol/L), same as hepatic VMDERMESTC=1.94e4; % dermal Vmaxc CPF-oxon -> TCPy (umol/hr/kg tissue) - 10-15% of liver this is, Jewell et al Tox Let 07- general skin esterase 10% of liver in humans - Beydon et al Tox In vitro, 2010 KDIS=0.; % TCP Excretion KE=0.024; % Optimized with Nolan 1984 IBLE1 and AE

% Protein Binding FBC=0.99; % 0.99 Lowe 2009 FBO=0.99; % 0.99 Lowe 2009 FUBO=0.01; FUBC=0.01;

% Timing/Integration MAXT=0.001; MINT=1.0e-006; REPTM=1.0E+6; %POINTS=1000;

% Molecular Wts (g/mol) MWC=350.6; MWO=334.5; MWP=198.0;% HCT HCTN=0.45; % 0.43 women, 0.47 men (Bresarb 1998)

% Partitioning Coef. (Lowe 2009) % CPF PFCN=250.0; % Fat/blood PHC=12.8; % Liver/blood PRC=16.5; % Richly perfused/blood PSC=3.85; % Slowly perfused/blood PDC=3.85; % Diaphram/blood PBC=16.5; % Brain/blood PSK=6.8; % Skin/Blood PSKL=200; %liquid/skin - actually a factor of both Q and partitioning - optimized PBL=1.0; % Blood/blood PLU=16.5;% Lung/blood = rapid PLAIR=7.6e5; %BARTELS 'generic' paper, calculated Poulen/Theil (25deg C) PPLA=3.85; %PLACENTA=SLOW % CPF-oxon PFON=75.0; % Fat/blood PHO=4.5; % Liver/blood PRO=5.6; % Richly perfused/blood PSO=1.8; % Slowly perfused/blood PDO=1.8; % Diaphram/blood PBO=5.6; % Brain/blood PBLO=1; % Blood/blood PLUO=5.6;% Lung/blood = rapid PLAIRO=7.6e5; %BARTELS 'generic' paper, calculated Poulen/Theil (25deg C), ASSUME =CPF PSKO=125;%liquid/skin - actually a factor of both Q and partitioning - =CPF PPLAO=1.8; %PLACENTA=SLOW

% BuChE activity (umol/hr/kg tissue) (Maxwell 1987) BBUCE=4.68e4; % 4.68E4 Maxwell 1987 DBUCE=2.64e4; HBUCE=3.0e4; BLBUCE=2.63e5; % 2.63E5 Sidell 1975 LUBUCE=8.6e4; %Maxwell, 87

% CaE activity (umol/hr/kg tissue) (Maxwell 1987) BRCE=2.88e5; % based on Hojring 1976 scaled by hepatic DACE=3.18e5; HECE=1.27e6; % based on Pope 2005, timchalk 02/Maxwell PLOCE=1e-99; % 0 Li 2005 LUECE=1.4e6; %Maxwell, 87

% AChE activity (umol/hr/kg tissue) (Maxwell 1987) BACHE=4.40e5; % 4.40E5 Maxwell 1987, BLACHE=1e-99; % 1248 Li 2005 & Brimijoin 1988 DACHE=7.74e4; HACHE=1.02e4; RBCHE=4.27e5; % 4.27E5 Albers 2009, LUACHE=2.28e4 ;%Maxwell, '87 -

% Esterase aging rates (1/h) KABBE=0.0113; KABCE=0.0113; KABCR=0.0113; KABLBE=0.0113; KABLCE=0.0113; KABLCR=0.0113; KADBE=0.0113; KADCE=0.0113; KADCR=0.0113; KAHBE=0.0113; KAHCE=0.0113;KAHCR=0.0113; KARBCE=0.0113; KALUCR=0.0113;

% Degradation of esterase (1/h) KDBBE=0.0024; KDBCE= 0.01; KDBCR=0.000754; KDBLBE=0.0024; KDBLCE=0.01; KDBLCR=0.0033; KDDBE=0.0024; KDDCE=0.01; KDDCR=0.001; KDHBE=0.0024; KDHCE=0.01; KDHCR=0.001; KDRBCE=0.01; KDLUCE=0.01;

% Inhibition of esterase (L/umol/h) KIBBE=2000; KIBCE=220; KIBCR=20; KIBLBE=2000; KIBLCE=220; KIBLCR=20; KIDBE=2000; KIDCE=220; KIDCR=20; KIHBE=2000; KIHCE=220; KIHCR=20; KIRBCE=100; KILUBE=2000; KILUCE=220; KILUCR=20;

% Reactivation of esterase (1/h) KRBBE=0.0014; KRBCE=0.014; KRBCR=0.014; KRBLBE=0.0014; KRBLCE=0.014; KRBLCR=0.014; KRDBE=0.0014; KRDCE=0.014; KRDCR=0.014; KRHBE=0.0014; KRHCE=0.014; KRHCR=0.014; KRRBCE=0.014; KRLUBE=0.0014; KRLUCE0=0.014; KRLUCR=0.014;

% Enzyme turnover rate (substrate hydrolysis/h/active site) (Maxwell 1987) TRCE=1.17e7; TRCR=1.086e5; TRBE=3.66e6;

% Blood flows (L/h/kg tissue) QBC=30.6; % Price 2003 QDC=85.2; % Luecke 2007 QFC=1.45; % Luecke 2007, Cowles 1971, Price 2003QHC=50.4; % Hepatic art, Price 2003 QSC=1.8; % Bone marrow, Price 2003 QRC=61.8; % Adreanal/spleen mean, Luecke 2007 SAF=1e-99; QPC=27.75; QSKC=12; %Approx skin blood flow to skin /kg of tissue

% turn off all model variability terms VMLV=0.0; VMBLV=0.0; VMHCPV=0.0; VMHHCOV=0.0; VINTTV=0.0; VINTOV=0.0; KIRBCEV=0.0; QHCV=0.0; HCTV=0.0; HECEV=0.0; KRHCRV=0.0; KRRBCEV=0.0; VHCV=0.0; KSIV=0.0; KDRBCEV=0; FATVAR=0.; VBLV=0.0; VHCV=0.0; KUNCERT=0.0;

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