PROGRAM NMP.ACSL

!PBPK MODEL FOR N

- METHYL PYRROLIDONE

!FINAL RAT MODEL (5/09)

!T.S. POET,P HINDERLITER. CHEMICAL DOSIMETRY GROUP, PNNL, RICHLAND, WA

!MODEL TRANSFERRED FROM SIMUSOLV TO ACSLXTREME FORMAT IN 08

!MODEL CONFIGURED FOR INHALATION (OPEN , WHOLE BODY/NOSE ONLY)

! IV, ORAL, DERMAL, AND IP ROUTES OF ADMINISTRATION.

!MODEL TRACKS DISPOSITION OF NMP AND 5

- HNMP.

!ASSUMPTIONS:

! (1) FLOW

- LIMI TED (ALL COMPARTMENTS)

! (2) METABOLISM OF NMP BY A SAT PATHWAY TO FORM 5HNP

! (3) METABOLISM OF HNP BY SATURABLE PATHWAY TO ETC.

! (5) METABOLISM OCCURS ONLY IN THE LIVER

! (6) TISSUE:BLOO D PART. COEFF. = HUMAN = KRISHNAN EQN

! UPDATED IN CMD FILE TO MEASURED IN

- HOUSE

! (7) 5HNP ELIMIN FROM MIXED VENOUS

- 1ST ORDER

! THIS DIFFERS FROM 02: URINE BY *GFR CLEARANCE FROM KIDNEY

! METAB RATE CONST. FROM REPORT

- UPDATED WITH LIT VAL UES IN CMD FILE

! PREG ADDED

- OTHER PARAMETERS CHANGED NOMINALLY TO HARMONIZE WITH

FETAL IPA MODEL OF

! GENTRY ET AL. REGU TOX PHARM 36:51

- 68, 2002

!

! Further updates by Paul Schlosser, US EPA in August and September 2013

and December 2014

INITIAL

! MODEL UNITS

! CONCENTRATION, MG/L

! FLOW, L/HR

! BODY WT, KG

CONSTANT BWINIT=0. ! PRE

- PREGNANCY BODY WEIGHT (KG)

CONSTANT RATS=1. !NUMBER OF ANIMALS IN EXPT

CONSTANT MWNMP=99.13 !MOL. WT. NMP, MG/MMOL

CONSTANT M WHP= 116.14 !MOL. WT. 5

- HNP, MG/MMOL

!BLOOD FLOWS

!FROM BROWN ET AL TOX IND HEALTH 97

!AND/OR FROM IPA MODEL OF GENTRY ET AL.,

! BLOOD FLOWS (FRACTION OF CARDIAC OUTPUT)

CONSTANT QCC = 0 ! CARDIAC OUTPUT (L/HR FOR 1 KG ANIMAL)

CONSTANT QPC = 0 ! ALVEOLAR VENT. RATE

CONSTANT QFATC = 0 ! FAT (NON

- PREGNANT)

CONSTANT QLIVC = 0 ! LIVER

CONSTANT QMAMC = 0 ! MAMMARY TISSUE (NON

- PREGNANT)

CONSTANT QSKNC = 0 ! SKIN

CONSTANT QUTRC = 0 ! UTERUS (NON

- PREGNANT)

CONSTANT QRAPC = 0 ! RAPID USE STATIC RAPID FOR RATS (MUST BE

CHANGED FOR HUMAN)! PERMEABILITY

- AREA PRODUCT (L/HR)

CONSTANT PAFC = 0.1 ! DIFFUSION ON FETAL SIDE OF PLACENTA

! T ISSUE VOLUMES (FRACTION OF BODY WEIGHT)

!FROM BROWN ET AL TOX IND HEALTH 97 FOR RATS

!OR FROM GENTRY ET AL

CONSTANT VLUC = 0 ! LUNG

CONSTANT VFATC = 0 ! FAT (NON

- PREGNANT)

CONSTANT VLIVC = 0 ! LIVER

CONSTANT VMA MC = 0 ! MAMMARY TISSUE (NON

- PREGNANT)

CONSTANT VRAPC = 0 ! RAPIDLY PERFUSED

CONSTANT VUTRC = 0 ! UTERUS (NON

- PREGNANT)

CONSTANT VBLC = 0 ! TOTAL BLOOD

! FOR PARENT MODEL, SKIN COMPARTMENT IS ONLY DEF INED AS DOSED SKIN

CONSTANT VSKC = 0.19 ! SKIN

CONSTANT SA = 0.01 !SURFACE AREA EXPOSED, SQ.CM

TSA = 906.*BWINIT**(2./3.) !TOTAL BODY SURFACE AREA, SQ.CM.

!MCDOUGAL ET AL. T.A.P.

85(1996) 286

IF (CONCL.GT.0.0) THEN

VSKCC = VSKC*SA/TSA

QSKCC = QSKNC*SA/TSA

ELSE

VSKCC = VSKC*SA/TSA

QSKCC = QSKNC*SA/TSA

ENDIF

! SLOWLY PERFUSED (DEFINED AS BALANCE OF TISSUES AND FLOWS)

VSC = 0.91

- (VLUC + VFATC + VLIVC + VMAM C + VRAPC + VUTRC + VBLC +

VSKCC)

! NOTE: 0.91 IS APPROX WHOLE BODY LESS BONE

QSC = 1.

- (QFATC + QLIVC + QMAMC + QRAPC + QUTRC + QSKCC)

! SCALED BLOOD FLOWS (L/HR)

QCINIT = QCC * (BWINIT**0.75)

QFATI = QFATC * QCINIT

QLIV = QL IVC * QCINIT

QMAMI = QMAMC * QCINIT

QRAP = QRAPC * QCINIT

QSKN = QSKCC * QCINIT

QSLW = QSC * QCINIT

QUTRI = QUTRC * QCINIT

! SCALED TISSUE VOLUMES (L)

VLU = VLUC * BWINIT

VFATI = VFATC * BWINIT

VLIVI = VLIVC * BWINIT

VRAP = VRAPC * BWINIT

VSLW = VSC * BWINIT

VMAMI = VMAMC * BWINIT

VUTRI = VUTRC * BWINIT

VSK = VSKCC * BWINITVBL = VBLC * BWINIT ! TOTAL BLOOD

VA = 0.25*VBL !ARTERIAL BLOOD

VV = 0.75*VBL !VENOUS BLOOD

! PREGNANCY PARAMETERS

CONSTANT NUMFET = 7.0 ! NUMBER OF FETUSES

CONSTANT PUPBW = 4500. ! BIRTH WEIGHT (MG)

CONSTANT VFETD18 = 1051.254 ! VOLUME OF FETUS AT DAY 18 ( ) OF

PREGNAN CY

! CONVERSION FACTORS

CONSTANT MGKG = 1.0E6 ! CONVERSION FACTOR FROM MG TO KG

!PARTITION COEFFICIENTS

!EXPERIMENTALLY MEASURED VALUES

CONSTANT PB=0. !NMP BLOOD:AIR

CONSTANT PF=0 !NMP FAT:BLOOD

- MEASURED

CONSTANT P L=0 !MEASURED

CONSTANT PR=0 !MEASURED LIVER

CONSTANT PS=0 !NOT MEASURED MUSCLE

- CORRECTED FOR FILTER

ERROR USING SKIN PROPORTIONALITY

CONSTANT PSKL=0 !MEASURED

CONSTANT PLU=0 !NMP LUNG:BLOOD

CONSTANT PSKA= 0 !NMP SKIN:AIR

CONSTANT PSKB=0 !NMP SKIN:BLOOD

CONSTANT PM=0 !MAMMARY, ESTIMATED FORM LIVER

CONSTANT PPLA=0

CONSTANT PUTR=0

!EXPERIMENTALLY MEASURED VALUES

CONSTANT PLHNP=0 !LIVER MEASURED

CONSTANT PBHNP=0 !ESTIMATED AVG OF "OTHER" TISSUES

CONSTANT PFHNP=0 !MEASURED

CONSTANT PPLHNP=0

!METABOLIC RATE CONSTANTS

CONSTANT KM=0 !MICHAELIS CONSTANT, MG/L

CONSTANT VMAXC=0 !MAX. ENZ. ACT., MG/HR/L

VMAX1 = VMAXC*BWINIT**0.75

!5HNP TO OTHE R METABS

CONSTANT KM2=0 !MICHAELIS CONSTANT, MG/L

CONSTANT VMAX2C=0 !MAX. ENZ. ACT., MG/HR/L

VMAX2 = VMAX2C*BWINIT**0.75

!URINARY ELIMINATION OF 5

- HNMP

- CLEARED FROM BLOOD

CONSTANT KLC=0

KL=KLC/(BWINIT**0.25)

CO NSTANT KLNC=0 !URINARY LOSS OF NMP, L/HR

KLN=KLNC/(BWINIT**0.25)

!FRACTIONAL ABSORPTIONCONSTANT FRACIN = 1 !FRACTIONAL UPTAKE OF NMP BY INHAL,START AT

65%

!OF ALVEOLAR

- AS IN AKESSON ET AL

1997

CONSTANT FRACOR = 1.0 !FRACTION ABSORBED ORALLY, INITALLY 100%

CONSTANT FRACF=1

! INITIAL CONDITIONS FOR CLOSED CHAMBER INHALATION

CONSTANT VCHC = 9E9 ! VOLUME OF CLOSED CHAMBER (L),START LARGE FOR

OPEN

CONSTANT KLOSS = 0.0 ! CHAMBER LOSS RATE /HR

!TIMING COMMANDS

CONSTANT TCHNG=6.0 !END OF INHAL EXPOSURE, HR

CONSTANT TSTOP=24.0 !END OF EXPERIMENT/SIMULATION, HR

CONSTANT MAXT=0.01 !MAXIMUM STEP SIZE, HR

CONSTANT MINT=1E

- 7

CONSTANT CINT = 0.2 !DATA LOGGING RATE /HR

CONSTANT GDDAYS=0.0 ! OFFSET FOR GESTATIONAL DAY SIMULATION

CONSTANT GDMONTHS=0.0 !OFFSET FOR HUMAN GD SIMULATION

!INITIAL EXPOSURE CONDITIONS

! EXPOSURE CONDITIONS BASED ON USER DEFINED INITIAL AMOUNTS OF C HEMICAL

(MG)

CONSTANT CONCPPM = 0.0 !AIR CONCENTRATION IN PPM!

constant concmgs = 0.0

! Used to set air conc'n as mg/m3

VCH = VCHC

- (RATS*BWINIT) !VOLUME OF OCCUPIED CHAMBER

CONCMG = CONCMGS/100 0 + CONCPPM*MWNMP/24451. !CONVERT PPM TO

MG/LITER

CONSTANT DOSEINTERVAL=24 !TIME

BETWEEN DAILY DOSES

constant concchppm0 = 0

! Initial ppm in closed chamber

conchmg0= concchppm0*MWNMP/24451.

ACHO = conchmg0 * VC H !INIT. AMT IN CHAMBER, MG!

!ORAL

CONSTANT KAS=1.0 !1ST ORDER RATE CONST FOR ORAL ABS from

stomach,HR

- 1

CONSTANT KAI=1 !1ST

ORDER RATE CONST FOR ORAL ABS from intestines,HR

- 1

CONSTANT KSI=1

CONSTA NT DOSE=0.0 !ORAL DOSE IN MG/KG BW

ODOSE = FRACOR*DOSE*BWINIT !CONVERT MG/KG BW TO MG

TOTAL(ORAL)

! ODOSE multiplied by FRACOR to reduce oral

bioavailability

constant dose2=0.0 ! ORAL

Dose in mg/kg BW, but total dose inc reases w/ BW

gavds=dose2*FRACOR*BWINIT ! Initial value for this

dose!FEED

CONSTANT KASF=1.0 !1ST ORDER RATE CONST FOR ORAL ABS,HR

- 1

CONSTANT DOSEF=0.0 !ORAL DOSE IN MG/KG BW in feed

!IV

CONSTANT I VDOSE=0.0 !IV DOSE, MG/KG NMP

!DERMAL

CONSTANT CONCL = 0.0 !CONC OF NMP IN LIQUID, MG/L

CONSTANT KPL = 0.0 !PERM COEFF FOR LIQUID, CM/HR

CONSTANT VLIQ = 1.0E

- 99 !INITIAL VOLUME APPLIED, L

CONSTANT DENSITY= 1.03

constant DSK=0.0 ! Initial amount (mg/kg BW) rubbed into

skin

ASKO=DSK*BWINIT

constant GDSTOP=15 ! Last GD of dermal dosing

constant twash=8.0 ! Wash time in Becci et al.

(1982) exposures

CONSTANT FAD=0.78 !FRAC no absorbed in Pa yan et al

!IN VITRO HUMAN VAN DYK ET AL. AIHA J 56: 651

- 660

!START WITH SMALL SA SO VSKE IS NON

- ZERO (USED IN DENOMINATOR OF

CSK CALCULATION)

!IP

CONSTANT IPDOSE = 0.0 !IP DOSE, MG/KG NMP

CONSTANT KIP=1.0 !1ST ORDER RATE OF ABS, HR

- 1

PDOSE = IPDOSE*BWINIT !TOTAL IP DOSE, MG

!DOSING SCHEDULE

if (DSK.GT.0.0) then

schedule SKWASH.AT.TWASH

ENDIF

SCHEDULE OFFD.AT.TCHNG !TURN OFF EXPOSURE AT TCHNG

CIZONE = 1.0 !START WITH INHALATION ON

IVZONE = 1.0 !START WITH IV ON

IF (CONCL.GT.0.0) THEN

DZONE = 1.0 !START WITH DERMAL ON

ELSE

DZONE = 0.0

ENDIF

constant tstart=0.2 ! offset start

- time for gavage dosing

schedule GAVD.at.T START

ALGORITHM IALG=2 !GEAR ALGORITHM

END

DYNAMIC

DERIVATIVE

!===============FETAL AND BW CHANGES W/PREGNANCY=======================

GDMONTH=GDMONTHS/0.64 !TO WAG GROWTH

HOURS = T

MINUTES = T * 60.0

DAYS = T / 24.0 + GDDAYS +GDMONTH

! VOLUME OF FAT (L)VFAT = VFATI * (1.0 + (0.0165 * DAYS))

! VOLUME OF FETUS (KG)

IF (DAYS.LT.10.0) THEN

VFET = (1.0e

- 8 + NUMFET * ((0.1206 * DAYS)**4.53)) / MGKG

ELSE IF (DAYS.LT.1 7.0) THEN

VFET = (1.0e

- 8 + NUMFET * ((1.5 * (DAYS

- 9))**2.8)) / MGKG

ELSE

VFET = (1.0e

- 8 + NUMFET * (VFETD18 + (((PUPBW

- VFETD18) / 4.0)

* (DAYS

- 17)))) / MGKG

ENDIF

! VOLUME OF MAMMARY TISSUE (L)

VMAM = VMAMI * (1.0 + (0.27 * DAYS))

! VOLUME OF PLACENTA (L)

IF (DAYS.LT.6.0) THEN

VPLA = 1.0e

- 8

ELSE IF (DAYS.LT.10.0) THEN

VPLA = (1.0e

- 8 + NUMFET * (8. * (DAYS

- 6.))) / MGKG

ELSE

VPLA = (1.0e

- 8 + NUMFET * ((32 * EXP(

- 0.23 * (DAYS

- 10)))+ (40

* (EXP(0.28 * (DAYS

- 10))

- 1)))) / MGKG

ENDIF

! VOLUME OF UTERUS (L)

IF (DAYS.LE.3.0) THEN

VUTR = VUTRI

ELSE

VUTR = VUTRI * (1.0 + (0.077 * ((DAYS

- 3.)**1.6)))

ENDIF

! VOLUME OF LIVER INCREASE !Corley et al CRC 03,BUELKE

- SAM ET AL '82 AND

OTHERS

IF (DAYS.LT.5.0) THEN

VLIV=VLIVI

ELSE

VLIV= VLIVI * (1.0 + (0.0455 * ((DAYS

- 5.0))))

ENDIF

! INCREASE IN BODY WEIGHT (KG)

BW = BWINIT + (VFAT

- VFATI) + VFET + (VMAM

- VMAMI) +

VPLA + (VUTR

- VUTRI)+(VLIV

- VLIVI)

! SCALED ALVEOLAR VENTILATION (L/HR)

QP = QPC * ((BW

- VFET

- VPLA)**0.75)

! INCREASE IN BLOOD FLOWS (L/HR)

QFAT = QFATI * (VFAT / VFATI)

QMAM = QMAMI * (VM AM / VMAMI)

QUTR = QUTRI * (VUTR / VUTRI)

! TOTAL BODY FOR HNMP

QB = QRAP+QSLW+QSKN+QMAM+QUTR !VB = VRAP+VSLW+VLU+VSK+VMAM+VUTR !

! BLOOD FLOW TO PLACENTA (L/HR)

IF (DAYS.LT.6.0) THEN

QPLA = 0.0

ELSE I F (DAYS.LT.10.0) THEN

QPLA = (NUMFET * (0.55 * (DAYS

- 6.0))) / 24

ELSE IF (DAYS.LE.12.0) THEN

QPLA = (NUMFET * (2.2 * EXP(

- 0.23 * (DAYS

- 10)))) / 24

ELSE

QPLA = (NUMFET * ((2.2 * EXP(

- 0.23 * (DAYS

- 10)))+ ((0.1 207 *

(DAYS

- 12.0))**4.36))) / 24

ENDIF

! INCREASED CARDIAC OUTPUT (L/HR)

QC = QFAT+QLIV+QSLW+QRAP+QSKN+QMAM+QPLA+QUTR

! SCALED PERMEABILITY

- AREA PRODUCT

PAF = PAFC * (VFET**0.75)

!==================FIRST MODEL FOR TRACKING NMP=========================

!EQUATIONS FOR ORAL GAVAGE DOSING

!note this is an oral model that expects some direct absorption to liver

and some transfered to intestine for absorption to liver

!this structure explains early peak and slow eli mination observed in

Midgely oral exposure data. Validated by Ghantous data

RAOA =

- (KAS * AO)

- (KSI*AO)

AO = ODOSE+ INTEG(RAOA,0.0) !AMT REMAINING TO BE ABS, MG

RAO=KAS*AO

OABS = INTEG(RAO,0.0)

RINTC=(KSI*AO)

- (KAI*AINTC) !RATE OF CHANGE IN INTESTINES

AINTC=INTEG(RINTC,0.0)

RAINTEST=KAI*AINTC !TRANSFER TO LIVER

OIBS=INTEG(RAINTEST,0.0)

!EQUATIONS FOR FEED DOSING

FDOSE = DOSEF*FRACF*BW !CONVERT MG/KG BW TO MG TOTAL(ORAL)

RAF = KASF * AF !*FRACF

AF = FDOSE

- INTEG(RAF,0.0) !AMT REMAINING TO BE ABS, MG!

FABS = INTEG(RAF,0.0)

!AL = AMOUNT NMP IN LIVER COMPARTMENT (MG)

RAL = QLIV*(CA

- CVL)+ RAIP + RAO + RAF

- RAML+RAINTEST

AL = INTEG(RAL, 0.0)

CVL = AL/(VLIV*PL)

RAML = (VMAX1*CVL)/(KM+CVL) !SATURABLE METABOLISM, MG/HR

AML = INTEG(RAML,0.0) !AMT NMP METAB BY SATURABLE PATH, MG

AML1B = RATS*AML*MWHP/MWNMP !TOT AMT HNP PRODUCED IN LIVER, MG

!EQUATIONS FOR IP DOSING

RAIP = KIP * AIP

AIP = INTEG(

- RAIP,PDOSE) !AMT REMAINING TO BE ABS, MG!IPABS = INTEG(RAIP,0.0)

!EQUATIONS FOR IV INFUSION

IVR = IVZONE*IVDOSE*BW/Tchng !RATE OF INFUSION, MG/HR using Tchng

TIV = INTEG(IVR,0.0) !TOTAL AMOUNT INJECTED, MG

! ARTERIAL BLOOD

RAAB = (QC * (CVLU

- CA))

- RAUNP

AAB = INTEG(RAAB, 0.0) !AMOUNT, MG

CA = AAB / VA !CONCENTRATION, MG/L

AAUCB = INTEG(CA, 0.0) !AUC, HR*MG/L

RAUNP = KLN*CA*VV !FIRST ORDER RATE OF LOSS (URINE

AUNP = INTEG(RAUNP,0.0)

! CHAMBER CONCENTRATION (MG/L)

RACH = (RATS * QP * CLEX)

- (FRACIN * RATS * QP * CI)

- (KLOSS *

ACH)

ACH = INTEG(RACH, ACHO)

! THE FOLLOWING CALCULATION YIELDS AN AIR CONCENTRATION EQUAL TO

! THE CLOSED C HAMBER VALUE IF A CLOSED CHAMBER RUN IS IN PLACE AND

! A SPECIFIED CONSTANT AIR CONCENTRATION IF AN OPEN CHAMBER RUN IS IN

PLACE

CCH = (ACH / VCH)! * CIZONE) + (CONCMG * (1.0

- CLON))

CCPPM = CCH *24451/MWNMP

CLOSS = INTEG(KLOSS * ACH,0.0)

CI = CCH*PULSE(0., DOSEINTERVAL,TCHNG) + CIZONE*CONCMG ! MG/L

! LUNGS

RALU = (QP * ((FRACIN * CI)

- CLEX)) + RVV

- (QC * CVLU)

ALU = INTEG(RALU, 0.0)

CLU = ALU / VLU !CONCENTRATION, MG/L

CVLU = CLU / PLU !EXITING CONCENTRATION, MG/L

! AMOUNT INHALED

RINH = FRACIN * QP * CCH *CIZONE

AINH = INTEG(RINH, 0.0) ! MG PER

AINHC = AINH * RATS ! MG FOR A GROUP OF RATS

! AMOUNT EXHALED

CLEX = CV / PB ! CONCENTR ATION, MG/L

RAEX = QP * CLEX

AEX = INTEG(RAEX, 0.0) ! AMOUNT, MG PER

AEXC = AEX * RATS ! AMOUNT, MG, FOR A GROUP OF RATS

!ASK = AMOUNT NMP IN SKIN TISSUES (MG) AND DERMAL DOSING

RASK = QSKN*(CA

- CSKV) + RADL

ASK = INTEG(RASK,ASKO) ! Initial value, ASKO, added for Becci

et al. (1982) exposures

CSK = ASK/VSK !'NMP IN SKIN, MG/L'CSKV = CSK/PSKB ! NMP IN VENOUS

BLOOD

CVSK3 = CSK*1000/MWNMP !'NMP IN CVSK, MICROMOL/L'

CON CL2=CONCL*FAD

CSURF=(CONCL2

- (ADL/VLIQ))*DZONE

RADL=(KPL*SA/1000.0)*((CSURF

- (CSK/PSKL))*DZONE

- (1.0

- DZONE)*(CSK/PSKA))

!

! 2ND term, (1.0

- DZONE)*(CSK/PSKA), allows for evaporative loss when

DZONE=0

ADL=INTEG(RADL,0.0)

! NOTE

- NO LOSS TERM. TRY WITHOUT OR ADD LOSS UP

- FRONT BY

SUBTRACTING

! AMOUNT RECOVERED FOR EACH STUDY WITH AMOUNT (CONC) ORIGINALLY

APPLIED

! "LOSS" OR STICKING PROBABLY ESSENTIALLY IMMEDIATE AND NOT

KINETIC

! REPORTS OF ~11

- 24% STICKING TO DRESSING

! AMOUNT IN FAT (MG)

RAFAT = QFAT * (CA

- CVFAT)

AFAT = INTEG(RAFAT, 0.0)

CFAT = AFAT / VFAT

CVFAT = CFAT / PF

! AMOUNT IN FETUSES (MG)

RAFET = PAF * (CPLA

- CFET)

AFET = INTEG(RAFET, 0.0)

CFET = AFET / VFET

AUCCFET = I NTEG(CFET, 0.0)

! AMOUNT IN UTERUS (MG)

RAUTR = QUTR * (CA

- CVUTR)

AUTR = INTEG(RAUTR, 0.0)

CUTR = AUTR / VUTR

CVUTR = CUTR / PUTR

! AMOUNT IN MAMMARY TISSUE (MG)

RAMAM = QMAM * (CA

- CVMAM)

AMAM = INTEG(RAMAM, 0.0)

CMAM = AMAM / VMAM

CVMAM = CMAM / PM

! AMOUNT IN PLACENTA (MG)

RAPLA = (QPLA * (CA

- CVPLA)) + (PAF * (CFET

- CPLA))

APLA = INTEG(RAPLA, 0.0)

CPLA = APLA / VPLA

CVPLA = CPLA / PPLA

!AS = AMOUNT IN SLOWLY PE RFUSED TISSUES (MG)

RAS = QSLW*(CA

- CVS)

AS = INTEG(RAS, 0.0)CVS = AS/(VSLW*PS)

CS = AS/VSLW

!AR = AMOUNT IN RAPIDLY PERFUSED TISSUES (MG)

RAR = QRAP*(CA

- CVR)

AR = INTEG(RAR, 0.0)

CVR = AR /(VRAP*PR)

CR = AR/VRAP

!MIXED VENOUS BLOOD

RVV = QC*CV

RV=(QFAT*CVFAT+QLIV*CVL+QSLW*CVS+QRAP*CVR+QSKN*CSKV+CVMAM*QMAM+CVPL

A*QPLA+QUTR*CVUTR+IVR)

- RVV

AV=INTEG(RV,0.0)

CV=AV/VV

AUCBB=INTEG(CV,0.0) !AUC, HR*MG/L

!

----------- MASS BALANCE NMP

--------------

BODY = (AFAT+AR+AS+AL+ASK+AV+ALU+AAB+APLA+AMAM+AUTR)

TMASS = RATS*(BODY + AML + AEX+AUNP+AFET)!COMPARE TO

!AINH FOR OC MASS BAL

!OR OABS FOR ORAL MASS BAL

!OR TIV FOR IV MASS BAL

!OR ADL FOR DERMAL LIQUID

MASBAL=TMASS/(AINH+OABS+TIV+ADL+OIBS+1E

- 9)

! CHECK BLOOD FLOWS

QTOT = QFATI + QLIV + QRAP + QSKN + QSLW + QUTRI +QMAM+QPLA

QRECOV = 100.0 * (QTOT / QC)

!===============SECOND MODEL FOR TRACKING HNP=====================

!ALHP = AMOUNT HNMP IN LIVER COMPARTMENT (MG)

RALHP = QLIV*(CAHP

- CVLHP)+ RAML1

- RAMLH

RAML1=RAML*MWHP/MWNMP

AML2B=INTEG(RAML1,0.0)

ALHP = INTEG(RALHP,0.0) !AMT IN MG HNMP, CORRECTED FOR MW

CVLHP = ALHP/(VLIV*PLHNP) !TOTAL HNMP

RAMLH = (VMAX2*CVLHP)/(KM2+CVLHP) !SATURABLE METABOLISM, MG/HR

AMLH = INTEG(RAMLH,0.0) !AMT HNMP METAB BY SATURABLE PATH, MG

rdose=ramlh/(BW** 0.75)

tdose=integ(rdose,0.0)

!ABHP = AMOUNT HNMP IN TISSUES (MG)

RABHP = QB*(CAHP

- CBSHP)

ABHP = INTEG(RABHP,0.0)

CBSHP = ABHP/(VB*PBHNP)

!AFHP = AMOUNT HNMP IN FAT (MG)

RFSHP = QFAT*(CAHP

- CVFHP)

AFHP = INTEG(RFSHP,0.0)

CVFHP = AFHP/(VFAT*PFHNP)!CVHP = MIXED VENOUS BLOOD CONC TOTAL HNMP (MG/L)

CRHP = (QLIV*CVLHP + QB*CBSHP + QFAT*CVFHP + QPLA*CVPLHP)

- QC*CVHP

- RAUHP

AVHP = INTEG (CRHP,0.0)

CVHP = AVHP/VBL

CAHP = CVHP

CVHP2 = CVHP*1000/MWHP !VENOU S BLOOD TOT CONC HNMP IN MICROM

AUCVHP = INTEG(CVHP2,0.0) !AUC HNMP VEN. BLOOD, MICROMOL*HR/L

! AMOUNT IN PLACENTA (MG)

RAPLHP = (QPLA * (CAHP

- CVPLHP)) + (PAF * (CFETHP

- CPLHP))

APLHP = INTEG(RAPLHP, 0.0)

CPLHP = APLHP / VPL A

CVPLHP = CPLHP / PPLHNP

! AMOUNT IN FETUSES (MG)

RAFETHP = PAF * (CPLHP

- CFETHP)

AFETHP = INTEG(RAFETHP, 0.0)

CFETHP = AFETHP / VFET

AUCFETHP = INTEG(CFETHP, 0.0)

!RATE OF ELIM IN THE URINE, RAUH P, FROM MIXED BLOOD

RAUHP = KL*CAHP*VA !FIRST ORDER RATE

AUHP = INTEG(RAUHP,0.0) !CUMULATIVE AMT HNMP IN URINE (MG), NOT

MGEQ

!

----------- MASS BALANCE

--------------

!

----------- MASS BALANCE 5

- HNMP SUBMODEL

--- -----------

BODYHP = (AFHP+ABHP+ALHP+AVHP+AFETHP+APLHP)*RATS

TMASHP = RATS*(AUHP + BODYHP +AMLH) !COMPARE TO AML1B

! CHECK BLOOD FLOWS 5HNMP COMPARTMENT

QTOTH = QLIV + QFAT + QB+QPLA

QRECOVH = 100.0 * (QTOTH / QC)

TERMT(T .GE. TSTO P) !

---- STATEMENT TO STOP EXECUTION

---

END !END OF DERIVATIVE

! The following discrete block allows for repeated gavage dosing, but

with

! the total dose (gavds) only updated every 3 days, per the protocol of

! Becci et al. (1982) and Sail lenfait et al. (2002); PMS 9

- 16

- 13

discrete GAVD

IF (ROUND(DAYS).EQ.9.0) gavds=FRACOR*dose2*BW

IF (ROUND(DAYS).EQ.12.0) gavds=FRACOR*dose2*BW

IF (ROUND(DAYS).EQ.15.0) gavds=FRACOR*dose2*BW

IF (ROUND(DAYS).EQ.18.0) gavds=FRACOR*dose2*BW

ODO SE=ODOSE+gavds

if (DAYS.LT.GDSTOP) schedule GAVD .at. (T+DOSEINTERVAL)

end

!EXPOSURE CONTROL

DISCRETE SKWASHASK = 0.0 ! Assume skin washing in Becci et al. (1982) removes all

NMP from skin

if (DAYS.LT.GDSTOP) SCHEDULE REAPPLY.AT.(T+DOSEINTER VAL

- TWASH)

END

DISCRETE REAPPLY

IF (ROUND(DAYS).EQ.9.0) ASKO=DSK*BW

IF (ROUND(DAYS).EQ.12.0) ASKO=DSK*BW

IF (ROUND(DAYS).EQ.15.0) ASKO=DSK*BW

IF (ROUND(DAYS).EQ.18.0) ASKO=DSK*BW

ASK = ASK + ASKO

SCHEDULE SKWASH.AT.(T+TWASH)

END

DISCRETE O FFD

IVZONE=0.0 !TURN IV OFF

CIZONE=0.0 !TURN INHAL EXPOSURE OFF

DZONE=0.0 !TURN OFF DERMAL

SCHEDULE OND.AT.(T+DOSEINTERVAL

- TCHNG)

END

DISCRETE OND

CIZONE=1.0 !TURN INHAL EXPOSURE ON

SCHEDULE OFFD.AT.(T+TCHNG)

END

END !END OF D YNAMIC

END !END OF PROGRAM