Document ID: EPA-HQ-OPP-2016-0062-0069
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-03-31T04:00Z

% 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=33.2
VML=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 2003
QHC=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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