EPA United States Environmental Protection Agency Office of Chemical Safety and Pollution Prevention Final Risk Evaluation for n-Methylpyrrolidone Supplemental PBPK Model Code CASRN: 872-50-4 December 2020 ------- This supplemental document presents model code for the rat and human NMP physiologically based pharmacokinetic (PBPK) models used in the Risk Evaluation for n-Methylpyrrolidone (NMP). The PBPK models of Poet et al. (2010) describe the toxicokinetics of NMP in rats and humans. EPA revised the models for use in the risk evaluation, and the models underwent scientific and technical evaluations consistent with those outlined in An umbrella Quality Assurance Project Plan (QAPP) for PBPK models (EPA. 2018). These PBPK models were initially evaluated and revised by EPA in 2013 (I v •! P \ „ < < l ). Further modifications and calibration were conducted by Dr. Torka Poet in 2014 (personal communication). In this update, additional data were considered to further calibrate and validate the model. Model calibration consists of using data to optimize parameters when those parameters are unknown or approximated, validation is used to show the fits of the model to other datasets. EPA then evaluated the version submitted by Dr. Poet in 2014 and made additional corrections and modifications as described in Appendix J of the Risk Evaluation for n-Methylpyrrolidone (NMP). Page 2 of 48 ------- Table of Contents 1 RAT NMP PBPK MODEL CODE 4 2 HUMAN NMP PBPK MODEL CODE 31 3 REFERENCES 48 Page 3 of 48 ------- 1 Rat NMP PBPK Model Code 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-LIMITED (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:BLOOD 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 VALUES IN CMD FILE ! PREG ADDED - OTHER PARAMETERS CHANGED NOMINALLY TO HARMONIZE WITH ! FETAL I PA MODEL OF GENTRY ET AL. REGU TOX PHARM 36:51-68, 2002 ! ! Updates by Paul Schlosser, U.S. EPA: Aug-Sept 2013, Dec 2014, Aug 2020 INITIAL ! MODEL UNITS ! CONCENTRATION, MG/L ! FLOW, L/HR ! BODY WT, KG CONSTANT BWINIT=0. ! PRE-PREGNANCY BODY WEIGHT (KG) constant GMULT=1. ! Multiplier for weight gain to match data. PS, U.S. EPA, July 6, 2020 CONSTANT RATS=1. ! NUMBER OF ANIMALS IN EXPT CONSTANT MWNMP=99.13 ! MOL. WT. NMP, MG/MMOL CONSTANT MWHP= 116.14 ! MOL. WT. 5-HNP, MG/MMOL ! BLOOD FLOWS ! FROM BROWN ET ALTOX IND HEALTH 97 ! AND/OR FROM IPA MODEL OF GENTRY ET AL., ! BLOOD FLOWS (FRACTION OF CARDIAC OUTPUT) Page 4 of 48 ------- 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 ! TISSUE VOLUMES (FRACTION OF BODY WEIGHT) ! FROM BROWN ET ALTOX 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 VMAMC = 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 DEFINED AS DOSED SKIN CONSTANT VSKC = 0.19 ! SKIN CONSTANT SA = 0.01 ! SURFACE AREA EXPOSED, SQ.CM TSA = 906.0*BWINIT**(2.0/3.0) ! 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 + VMAMC + 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) Page 5 of 48 ------- QFATI = QFATC * QCINIT QLIVI = QLIVC * QCINIT ! QLIV now calculate in DERIV to account for growth, PMS 3/11/20 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 * BWINIT VBL = 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 PREGNANCY ! CONVERSION FACTORS CONSTANT MGKG = 1.0E6 ! CONVERSION FACTOR FROM MG TO KG ! PARTITION COEFFICIENTS ! Values set in parameter .m file CONSTANT PB=0 ! NMP BLOOD:AIR CONSTANT PF=0 ! NMP FAT:BLOOD - MEASURED CONSTANT PL=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 Page 6 of 48 ------- ! 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*BWI NIT* *0.75 15HNPTO OTHER METABS CONSTANT KM2=0 ! MICHAELIS CONSTANT, MG/L CONSTANT VMAX2C=0 ! MAX. ENZ. ACT., MG/HR/L VMAX2 = VMAX2C*BWI NIT* *0.75 ! URINARY ELIMINATION OF 5-HNMP - CLEARED FROM BLOOD CONSTANT KLC=0 KL=KLC/(BWI NIT* *0.25) CONSTANT KLNC=0 ! URINARY LOSS OF NMP, L/HR KLN=KLNC/(BWI NIT* *0.25) ! FRACTIONAL ABSORPTION CONSTANT 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=lE-7 CONSTANT CINT = 0.2 ! DATA LOGGING RATE /HR CONSTANT GDDAYS=0.0 ! OFFSET FOR GESTATIONAL DAY SIMULATION ! INITIAL EXPOSURE CONDITIONS ! EXPOSURE CONDITIONS BASED ON USER DEFINED INITIAL AMOUNTS OF CHEMICAL (MG) Page 7 of 48 ------- 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/IOOO.O + CONCPPM*MWNMP/24451.0 ! CONVERT PPM TO MG/LITER CONSTANT DOSEINTERVAL=24.0 ! TIME BETWEEN DAILY DOSES constant concchppmO = 0.0 ! Initial ppm in closed chamber conchmg0= concchppmO* MWN MP/24451.0 ACHO = conchmgO * VCH ! INIT. AMT IN CHAMBER, MG ! ! ORAL CONSTANT KAS=1.0 ! 1ST ORDER RATE CONST FOR ORAL ABS from stomach, HR-1 CONSTANT KAI=1.0 ! 1ST ORDER RATE CONST FOR ORAL ABS from intestines, HR-1 CONSTANT KSI=1.0 CONSTANT DOSE=0.0 ! ORAL DOSE IN MG/KG BW ODOSE = FRACOR* DOSE*BWI NIT ! 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 increases 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 IVDOSE=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 Payan et al ! IN VITRO HUMAN VAN DYK ET AL. AIHAJ 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 Page 8 of 48 ------- ! DOSING SCHEDULE if (DSK.GT.0.0) then schedule SKWASH.AT.TWASH ENDIF SCHEDULE OFFD.AT.TCHNG CIZONE = 1.0 ! START WITH IVZONE = 1.0 ! START WITH IF (CONCL.GT.O.O) THEN DZONE = 1.0 ! START WITH ELSE DZONE = 0.0 ENDIF constant tstart=0.2 ! offset start-time for gavage closing CONSTANT GSTART=0.0 ! Days after start of exposure when gestation starts schedule GAVD.at.TSTART ALGORITHM IALG=2 ! GEAR ALGORITHM END DYNAMIC DERIVATIVE !===============FETAL AND BW CHANGES W/PREGNANCY======================= DAYS = MAX((T / 24.0 + GDDAYS - GSTART), 0.0) ! VOLUME OF FAT (L) VFAT = VFATI * (1.0 + (0.0165 * DAYS * GMULT)) ! 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.17.0) 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 * GMULT)) ! 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 * (8.0 * (DAYS - 6.0))) / MGKG !TURN OFF EXPOSURE AT TCHNG INHALATION ON IV ON DERMAL ON Page 9 of 48 ------- ELSE VPLA = (1.0e-8 + NUMFET * ((32.0 * EXP(-0.23 * (DAYS -10.0)))+ (40.0 * (EXP(0.28 * (DAYS -10.0)) - 1.0))))/ MGKG ENDIF ! VOLUME OF UTERUS (L) IF (DAYS.LE.3.0) THEN VUTR = VUTRI ELSE VUTR = VUTRI * (1.0 + (0.077 * ((DAYS - 3.0)**1.6)) * GMULT) ENDIF ! VOLUME OF LIVER INCREASE ICorley 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) * GMULT)) 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 * (VMAM / VMAMI) QUTR = QUTRI * (VUTR / VUTRI) QLIV = QLIVI * (VLIV / VLIVI) ! 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 IF (DAYS.LT.10.0) THEN QPLA = (NUMFET * (0.55 * (DAYS - 6.0))) / 24.0 ELSE IF (DAYS.LE.12.0) THEN QPLA = (NUMFET * (2.2 * EXP(-0.23 * (DAYS -10.0)))) / 24.0 ELSE QPLA = (NUMFET * ((2.2 * EXP(-0.23 * (DAYS -10.0)))+ ((0.1207 * (DAYS -12.0))**4.36))) / 24.0 Page 10 of 48 ------- 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 elimination observed in Midgely oral ! exposure data. Validated by Ghantous data RAO=KAS*AO RAOA = -RAO-(KSI*AO) AO = ODOSE+ INTEG(RAOA,0.0) ! AMT REMAINING TO BE ABS, MG OABS = INTEG(RAO,0.0) RAINTEST=KAI*AINTC ! TRANSFER TO LIVER RINTC=(KSI*AO)-RAINTEST ! RATE OF CHANGE IN INTESTINES AINTC=INTEG(RINTC,0.0) OIBS=INTEG(RAINTEST,0.0) ! EQUATIONS FOR FEED DOSING RFDOSE = DOSEF*FRACF*BW*PULSE(0.0,24.0,12.0) *2/24.0 ! Convert to mg/h for continuous feed dosing RABS = KSI * AF ! Rate added to amount in intestines RAF = RFDOSE - RABS AF = INTEG(RAF,0.0) ! AMT intestinal lumen ! AL = AMOUNT NMP IN LIVER COMPARTMENT (MG) RAL = QLIV*(CA - CVL)+ RAIP + RAO + RABS - 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 ! Page 11 of 48 ------- 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) 1AMOUNT, MG CA = AAB / VA ! CONCENTRATION, MG/L AAUCB = INTEG(CA, 0.0)! AUC, HR*MG/L RAUNP = KLN*CA*VA ! 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 CHAMBER 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 *24451.0/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 ! CONCENTRATION, MG/L RAEX = QP * CLEX AEX = INTEG(RAEX, 0.0) ! AMOUNT, MG PER AEXC = AEX * RATS ! AMOUNT, MG, FOR A GROUP OF RATS Page 12 of 48 ------- ! 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*1000.0/MWNMP ! 'NMP IN CVSK, MICROMOL/L' CONCL2=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 ~ll-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 = INTEG(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) Page 13 of 48 ------- CPLA = APLA/VPLA CVPLA = CPLA / PPLA ! AS = AMOUNT IN SLOWLY PERFUSED 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+CVPLA*QPLA+QUT R*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 ! ORTIV FOR IV MASS BAL ! OR ADL FOR DERMAL LIQUID MASBAL=TMASS/(AINH+OABS+TIV+ADL+OIBS+lE-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 Page 14 of 48 ------- 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*1000.0/MWHP ! VENOUS 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/VPLA 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, RAUHP, 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 Page 15 of 48 ------- ! CHECK BLOOD FLOWS 5HNMP COMPARTMENT QTOTH = QLIV + QFAT + QB+QPLA QRECOVH = 100.0 * (QTOTH / QC) TERMT(T .GE. TSTOP) !—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 Saillenfait et al. (2002); PMS 9-16-13 discrete GAVD IF (ROUND(DAYS).EQ.9.0) IF (ROUND(DAYS).EQ. 12.0) IF (ROUND(DAYS).EQ. 15.0) IF (ROUND(DAYS).EQ. 18.0) ODOSE=ODOSE+gavds if (DAYS.LT.GDSTOP) schedule GAVD .at. (T+DOSEINTERVAL) gavds=FRACOR*dose2*BW gavds=FRACOR*dose2*BW gavds=FRACOR*dose2*BW gavds=FRACOR*dose2*BW end ! EXPOSURE CONTROL DISCRETE SKWASH ASK = 0.0 ! Assume skin washing in Becci et al. (1982) removes all NMP from skin if (DAYS.LT.GDSTOP) SCHEDULE REAPPLY.AT.(T+DOSEINTERVAL-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 OFFD 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 Page 16 of 48 ------- END ! END OF DYNAMIC END ! END OF PROGRAM Payan and Wells IV 14.m %PROCED WELLS - IV %WELLS AND DIGENIS 1988 prepare @clearT CV ratparam TCHNG=0.0167; CINT=0.01; BWINIT=0.35; IVDOSE=45; TSTOP=12; GDDAYS=0; start @nocallback tl=_t; cl=_cv; IVDOSE=0.1; GDDAYS=1; start @nocallback MASBAL % DATA WELLS (T,CV,Poet 2013 CV) DWELLS = [0.08 92 0.17 69 0.25 62 0.33 59 0.5 58 0.75 58 1 55 1.5 52 2 50 4 40 6 35]; % DATA PAYAN (T,CV,) D PAYAN = [0.080.16 0.17 0.15 0.35 0.13 0.67 0.13 1 0.12 1.5 0.11 2 0.11 3 0.1 4 0.07 6 0.014]; plot(tl, cl, DWELLS(:,1), DWELLS(:,2), ... _t, _cv, DPAYAN(:,1), DPAYAN(:,2), 'ivplasma.aps') Page 17 of 48 ------- Oral Midgely and Ghant 14. use ratparam prepare @clear @all GO50M =[0.017 2.212; 0.05 4.653; 0.08 15.267; 0.5 11.097; 1 29.789; 2 15.840; 4 13.644; 8 5.875; 12 2.441]; %(T,CV,AUHP) GO50F =[0.25 20.600 NaN 0.50 28.793 NaN; 1.00 38.044 NaN; 1.50 21.393 NaN; 2.00 31.028 NaN; 4.00 20.942 NaN; 6.00 12.005 NaN; 8.00 5.178 NaN; 12.00 NaN 4.46; 24.00 NaN 6.54; 36.00 NaN 6.71; 48.00 NaN 6.83; 72.00 NaN 6.92; 96.00 NaN 6.97; 120.00 NaN 7.00]; %(T,CV) MIDG =[0.25 45.2 NaN; 0.5 56.25 NaN; 2 65.00 NaN; 3.5 58.00 NaN; 6 46 1.66; 8 33.00 NaN; 12 6.1 NaN; 24 NaN 8.40; 72 NaN 8.70; 120 NaN 8.82] % MIDGLEY ET AL, 1992 ------- BWINIT=0.216; D0SE=112; TSTOP=124; DOSEINTERVAL=148; CINT=0.1; start @nocallback ares=[_auhp]; cres=[_cv]; % Ghantous -males BWINIT=0.262; DOSE=50; start @nocallback cres=[cres _cv]; tl=_t; % Ghantous - females preg_rat_params GDDAYS=0; CINT=0.1; TSTOP=124; BWINIT=0.221; DOSE=50*0.955; start @nocallback ares=[ares _auhp]; % Note, dose is as reported, minus "feed residue", which was 4.5% of dose for % the females. Also, while methods to measure dosing solution NMP are % described, no value is given so the target is assumed and this is based on mass plot(tl,ares, MIDG(:,l),MIDG(:,3),GO50F(:,l), GO50F(:,3),'figGHANTorAUHP.aps') plot(tl,cres(:,l), MIDG(:,l),MIDG(:,2),tl,cres(:,2), G050M(:,l),G050M(:,2),_t,_cv,G050F(:,l),G050F(:,2),'figGHANTorCV.aps') Payan 2002 IV5HNMP 14.m prepare @clear T AUHP CVHP ratparam TCHNG=0.01; TSTOP=78; BWINIT=0.275; CINT=0.1; holdcvhp=[]; holdauhp=[]; for IVDOSE=[0.1 1 10 100 500] start @nocallback holdcvhp=[holdcvhp _cvhp]; holdauhp=[holdauhp _auhp]; end %Data, 5HNMP peak mg/kg (T, CVHP, dose in order 0.1,1,10,100,500) %note 500 above curve %(T,CVHP) P5H =[5 0.035; 4 0.38; 4 3.3; 8 23.7]; %Data, 5HNMP total in urine over 3 days (T, CVHP, dose in order 0.1,1,10,100,500) P5HU=[72 0.01 0.11 1 13 68]; plot(_t,holdcvhp, P5H(:,1),P5H(:,2), 'IV plasma 5HNMP.aps') Page 19 of 48 ------- plot(_t,holdauhp(:,l:3), P5HU(:,1),P5HU(:,2),P5HU(:,1),P5HU(:,3),P5HU(:,1),P5HU(:,4), 'Payan 2002 IV urine 5HNMP.aps') plot(_t,holdauhp(:,3:5), P5HU(:,1),P5HU(:,4),P5HU(:,1),P5HU(:,5),P5HU(:,1),P5HU(:,6), 'Payan 2002 IV urine 5HNMP high.aps') Payan 2003 Dermal plasma 14.m prepare @clearT CV ratparam %payan dermal exposures: Payan et al. DMD 03 BWINIT=0.220; TCHNG=72; TSTOP=48; SA=10; VLIQ=200e-6; CONCL=1060000; CINT=0.5; start @nocallback % DATA PAYAN (T,Payan 2003 CVHP) PAYAN = [0.25 166.86 0.75 276.04 1 354.32 1.5 418.18 2 475.86 3 535.60 3.5 556.20 4 593.28 5 570.62 6 578.86 8 564.44 10 529.42 24 107.53 26 111.65 30 59.95]; plot(_t, _cv, PAYAN (:,1), PAYAN (:,2), 'Fig 7 Payan 2003 Dermal plasma.aps') Poet2013_Figl_gestation growth.m prepare @clear @all ratparam preg_rat_params % Added by Paul Schlosser (PS), U.S. EPA, 05-01-2013 BWINIT=0.232; DOSEINTERVAL=24; TSTOP=528; TCHNG=6, GDDAYS=0, MAXT=1; BWINIT=0.262; % Matches GD6 BW of controls in Saillenfait et al. 2002; PS 5-2-13 VFETD18 = 1051.254; % Default from .csl file; PS 5-2-13 start @nocallback Page 20 of 48 ------- plot(_t/24, _bw, _t/24, _vfat, _t/24, _vmam, _t/24, _vpla, _t/24, _vfet, 'pregphyschanges.aps') simres=[_t/24, _bw, _vfat, _vmam, _vpla, _vfet]; save simres @file='pregSims.csv' @format=ascii @separator=comma Ghantous_1995 inhalation 14.m use ratparam prepare @clear @ALL VCHC=1.0e+9; TSTOP=144; TCHNG=6; DOSEINTERVAL=144; %female rat CONCPPM=104.3, BWINIT=0.235; start @nocallback holdauhp=[_auhp]; holdcv=[_cv]; % male rat CONCPPM=104.3, BWINIT=0.216; start @nocallback holdcv=[holdcv_cv]; holdauhp=[holdauhp _auhp]; %DATA GHANTIN10F (T,AUHP) GHANTIN10F=[18 0.83; 30 1.18; 42 1.25; 54 1.29; 78 1.32; 126 1.35]; %DATA GHANTIN10M (T,AUHP) GHANTIN10M=[18 0.86; 30 1.09; 42 1.16; 54 1.19; 78 1.24; 126 1.27]; %DATA GIN100M (T,CV,AUHP) GIN100M=[0.251.13 NaN; 0.5 3.83 NaN 1 8.61 NaN 2 10.67 NaN 4 20.47 NaN 6 10.18 NaN 7 17.87 NaN Page 21 of 48 ------- 8 2.44 NaN; 10 3.36 NaN; 18.00 NaN 5.21; 30.00 NaN 6.31; 42.00 NaN 6.72; 54.00 NaN 6.88; 78.00 NaN 7.12; 102.00 NaN 7.29; 126.00 NaN 7.41] %DATA GIN100F (T,CV,AUHP) GIN100F=[0.25 4.22 NaN; 0.50 8.16 NaN; 1.00 17.26 NaN; 2.00 20.04 NaN; 4.00 52.42 NaN; 6.00 49.28 NaN; 7.00 30.06 NaN; 8.00 49.30 NaN; 10.00 21.79 NaN; 12.00 4.56 NaN; 18 NaN 5.78; 30 NaN 6.99; 42 NaN 7.22; 54 NaN 7.29; 78 NaN 7.48; 102 NaN 7.62; 126 NaN 7.68] plot(_t,holdcv, GIN100F(:,l),GIN100F(:,2),GIN100M(:,l),GIN100M(:,2),'figGHANTINCV.aps') Becci_1982_dermal.m % Internal dose calculations for Becci et al. (1982) inhalation study % Exposure levels (CONCMGS) are those used by Saillenfait plus an external dose BMCL % Paul Schlosser, U.S.EPA, Aug. 28, 2013 % NOAEL= 237mg/kg/day based on a developmental study of dermal exposure of rats % to NMP for 8-hrs, GD 6 to 15 (Becci et al, 1982). use ratparam use preg_rat_params GDDAYS=6.01; TSTOP=14*24; CINT=0.01; BWINIT=0.2375; TWASH=8; DOSEINTERVAL=24; SA=25; GDSTOP=19; res = [0,0,0,0]; prepare @clear @all Page 22 of 48 ------- for DSK=[75 237 750] start @nocallback apk = max(_aucbb(_t>24)-_aucbb(_t<(TSTOP-24))); res=[res; [DSK,apk,(AUCBB*24/TSTOP),max(_cv)]] end plot(_days,_cv) DAILY_SAILLENFAIT_METRICS.m % Simulations of Saillenfait et al. (2002) oral gavage bioassay %t poet changes indicated. use ratparam use preg_rat_params prepare @clear @all % T DAYS AUCBB CV BWINIT=0.259; % T Poet - GD6 average (257-262) GDDAYS=6.01; TSTART=0.2; TSTOP=TSTART+24; CINT=0.01; GDSTOP=20; DOSEINTERVAL=24; AUCAVG=[]; AUCTOT=[]; DAY=[]; CMAX=[]; dose=[]; for DOSE2=128.5 %[125 250 500 750] for id=2:15 TSTOP=TSTART+id*24; dose=[dose; DOSE2]; start @nocallback AUCAVG=[AUCAVG; AUCBB*24/TSTOP]; %NOTE, THIS WILL BE OFF BY THE 0.2 HR OFFSET FOR DOSING AUCTOT=[AUCTOT; AUCBB]; DAY=[DAY; (TSTOP-TSTART)/24]; CMAX=[CMAX; max(_cv)]; end end [dose, DAY, AUCAVG, CMAX] DAILY_SAILLENFAIT_INHALATION_METRICS.m % Simulations of Sail lenfait et al. (2002) oral gavage bioassay %t poet changes indicated. use ratparam use preg_rat_params prepare @clear @all % T DAYS AUCBB CV BWINIT=0.270 % T Poet - GD6 average (268-273) GDDAYS=6.01; CINT=0.01; TCHNG=6; DOSEINTERVAL=24; AUCAVG=[]; AUCTOT=[]; DAY=[]; CMAX=[]; conc=[]; Page 23 of 48 ------- %CONCMGS=[122 243 302 487] for CONCPPM = [30 60 121] for d=15 TSTOP=TSTART+d*24; conc=[conc; CONCPPM]; start @nocallback AUCAVG=[AUCAVG; AUCBB*24/TSTOP]; %NOTE, THIS WILL BE OFF BY THE 0.2 HR OFFSET FOR DOSING AUCTOT=[AUCTOT; AUCBB]; DAY=[DAY; (TSTOP-TSTART)/24]; CMAX=[CMAX; max(_cv)]; end end plot(_t,_cv) plot(_days,_aucbb) [cone, DAY, AUCTOT, AUCAVG, CMAX] DAILY_BECCI_METRICS.m % Internal dose calculations for Becci et al. (1982) inhalation study % Exposure levels (CONCMGS) are those used by Saillenfait plus an external dose BMCL % Paul Schlosser, U.S.EPA, Aug. 28, 2013 % NOAEL= 237mg/kg/day based on a developmental study of dermal exposure of rats % to NMP for 8-hrs, GD 6 to 15 (Becci et al, 1982). use ratparam use preg_rat_params GDDAYS=6.01; TSTOP=l*24; CINT=0.005; BWINIT=0.263; TWASH=8; DOSEINTERVAL=24; SA=25; VLIQ=le55; prepare @clear @all DOSEINTERVAL=24; AUCAVG=[]; AUCTOT=[]; DAY=[]; CMAX=[]; dose=[]; %for DSK=[75 237 750] DSK=166.5 for id=[2 10] %2:10 TSTOP=TSTART+id*24; start @nocallback AUCAVG=[AUCAVG; AUCBB*24/TSTOP]; %NOTE, THIS WILL BE OFF BY THE 0.2 HR OFFSET FOR DOSING AUCTOT=[AUCTOT; AUCBB]; DAY=[DAY; (TSTOP-TSTART)/24]; CMAX=[CMAX; max(_cv)]; dose=[dose; DSK]; end [dose, DAY, AUCAVG, CMAX] Page 24 of 48 ------- DAILY_SOLOMON_INALATION_METRICS.m % Simulations of Solomon et al. 1995/Staples - INHALATION use ratparam use preg_rat_params prepare @clear @all % T DAYS AUCBB CV BWINIT=0.310 % T Poet - GD6 average (268-273) GDDAYS=0.01; CINT=0.01; TCHNG=6; DOSEINTERVAL=24; TSTOP=TSTART+24 AUCAVG=[]; AUCTOT=[]; DAY=[]; CMAX=[]; conc=[]; for CONCPPM=[10, 51, 116] for d=20 %2:20 TSTOP=TSTART+d*24; start @nocallback AUCAVG=[AUCAVG; AUCBB*24/TSTOP]; %NOTE, THIS WILL BE OFF BY THE 0.2 HR OFFSET FOR DOSING AUCTOT=[AUCTOT; AUCBB]; CMAX=[CMAX; max(_cv)]; DAY=[DAY; (TSTOP-TSTART)/24]; conc=[conc; CONCPPM] end end plot(_t,_cv) plot(_days,_aucbb) [cone, DAY, AUCAVG, CMAX] DAILY_THORNTON_FEED_METRICS.m % Simulations of THORNTON FEED STUY %ESTIMATED ASSUMING A 12 HR "INFUSION" RATE FOR AN ORAL DOSE. use ratparam use preg_rat_params prepare @clear @all % T DAYS AUCBB CV BWINIT=0.264 % T Poet - GD6 average (257-262) GDDAYS=0.01; TSTART=0.2; TSTOP=TSTART+24; CINT=0.1; KAS=0.083, KAI=0, DOSEF=554 %57%171%554 AUCAVG=[]; AUCTOT=[]; DAY=[]; CMAX=[]; dose=[]; for id=l:20 TSTOP=TSTART+id*24; start @nocallback AUCAVG=[AUCAVG; AUCBB*24/TSTOP]; dose=[dose; DOSEF]; %NOTE, THIS WILL BE OFF BYTEH 0.2 HR OFFSET FOR DOSING AUCTOT=[AUCTOT; AUCBB]; DAY=[DAY; (TSTOP-TSTART)/24]; CMAX=[CMAX; max(_cv)]; end Page 25 of 48 ------- plot(_t,_cv) plot(_days,_aucbb) [dose, DAY, AUCAVG, CMAX] Daily_Becci_metrics_revised.m % Internal dose calculations for Becci et al. (1982) inhalation study % Exposure levels (CONCMGS) are those used by Saillenfait plus an external dose BMCL % Paul Schlosser, U.S.EPA, Aug. 28, 2013 % NOAEL= 237mg/kg/day based on a developmental study with dermal exposure of rats % to NMP for 8-hrs, GD 6 to 15 (Becci et al, 1982). % Simplified code with for-loops Chris Brinkerhoff Aug 6, 2014 use ratparam use preg_rat_params GDDAYS=6.01; CINT=0.01; TSTART=0; TSTOP=24; GDSTOP=19; BWINIT=0.263; TWASH=8; DOSEINTERVAL=24; SA=25; VLIQ=le55; prepare @clear @all DSKS=[75 237 750]; %DSKS=402; %DSKS=237; lastday=14; res = []; DAILYAUC=[]; AUCTOT=[]; for j = l:length(DSKS) DSK = DSKS(j) for i = l:lastday TSTOP=TSTART+i*24 start @nocallback AUCTOT((j-l)*lastday+i) = AUCBB; if i == 1 DAILYAUC((j-l)*lastday+i) = AUCBB; else DAILYAUC((j-l)*lastday+i) = AUCBB - AUCTOT((j-l)*lastday+i-l); end res(:,(j-l)*lastday+i) = [DSK; i; max(_cv); DAILYAUC((j-l)*lastday+i)]; end end res(:,[l 14 15 28 29 42]) %save res @file='Becci_1982_dermal_results_2nd_time.csv' @format=ascii @separator=comma Page 26 of 48 ------- Exxon91.m use ratparam use preg_rat_params prepare @clear @all % T DAYS AUCBB CV CINT=1; TSTART=0; % Used for bolus dosing, not needed here GSTART=7; % Day after start of exposure when gestation begins % GSTART should be high enough to reach periodicity or steady state TSTOP=(GSTART+21)*24; TCHNG=TSTOP+l; % Allows 21 days of gestation BWINIT=mean([324.3 305.4 281.5])/1000; NUMFET=14; gdosestart = (GSTART+6)*24; %Time (h) to start calculating pregnancy average concentration gesthr=TSTOP-gdosestart; % Total hours over which pregnancy dose is calculated DOSEF=95.4; start @nocallback [BWINIT, DOSEF, NUMFET, _bw(TSTOP-24), (_aucbb(find(_t==TSTOP))- _aucbb(find(_t==gdosestart)))*24/gesthr] return TSTOP=GSTART*24; % Don't simulate pregnancy for juvenile animal/growth period TCHNG=TSTOP+l; % TCHNG turns off dosing if < TSTOP, for analyzing stop-dose studies doses = [50 160 500]; % mg/kg/d 27.93 % tres = [0, doses]; % First row of results table %for BWINIT=[50 100 150 200 300 400]/1000; for BWINIT=[50 250 350 450]/1000; rres = BWINIT; % Start row of results table for DOSEF=doses start @nocallback sscheck = _cv(GSTART*24)/_cv((GSTART-l)*24) -1; % check for periodicity/SS, should be ~ 0 rres = [rres, (_aucbb(TSTOP) - _aucbb(TSTOP-24))/24]; % AUC for last day of exposure %rres = [rres, mean(_cv(((GSTART-l)*24):(GSTART*24)))]; % AUC for last day of exposure end %plot(_t/24,_cv) tres = [tres; rres]; % Append results row end tres, doses(l)*202/rres(2) TSTOP=(GSTART+21)*24; TCHNG=TSTOP+l; % Allows 21 days of gestation "Simulations for gestational exposure P2/F2A" BWs=[324.3 305.4 281.5]/1000; % Initial BWs for each exposure group, from Table 53 Page 27 of 48 ------- % Below calculates mean intake (dose rate) for each group, from values for GD 6-20 in Table 67. doses=[mean([55.1 52.5 51.4 50.9]), mean([170.9 167.8 162.9 165.4]), mean([514.3 524.6 479.7 457.8])]; nfet=[17 19 14]; % # of fetuses for each dose group, chose to approximately match GD 20 BW % *** nfet does *NOT* match the observed number born, reported by Exxon (1991). % nfet is the # for which the combined maternal/fetal BW at GD 20 most closely matches % the maternal BW in Table 53 (Exxon, 1991) at GD 20. p2f2a=[]; % empty results array for n=l:3; BWINIT=BWs(n); DOSEF=doses(n); NUMFET=nfet(n); % Assign group input values start @nocallback sscheck = _cv(GSTART*24)/_cv((GSTART-l)*24) -1; % check for periodicity/SS @ GSTART, should be ~ 0 % Below appends inputs and results to array p2f2a = [p2f2a; [BWINIT, DOSEF, NUMFET, _bw(TSTOP-24), (_aucbb(find(_t==TSTOP))- _aucbb(find(_t==gdosestart)))*24/gesthr]]; % AUC/time = avg cone %p2f2a = [p2f2a; [BWINIT, DOSEF, NUMFET, _bw(TSTOP-24), (AUCBB- _aucbb(find(_t==gdosestart)))*24/gesthr]]; % AUC/time = avg cone %p2f2a = [p2f2a; [BWINIT, DOSEF, NUMFET, _bw(TSTOP-24), (AUCBB- _aucbb(find(_t==gdosestart)))/15]]; % AUC/DAYS = avg auc plot(_t/24,_cv) end p2f2a "Simulations for gestational exposure P2/F2B" BWs=[370.6 353.6 318.7]/1000; % Initial BWs for each exposure group, from Table 56 % Below calculates mean intake (dose rate) for each group, from values for GD 6-20 in Table 69. doses=[mean([53.7 51.2 47.9 44.6]), mean([165.6 164.8 152.9 143.5]), mean([508.5 491.1 460.4 406.5])]; nfet=[18 19 12]; % # of fetuses for each dose group, chose to approximately match GD 20 BW % *** nfet does *NOT* match the observed number born, reported by Exxon (1991). % nfet is the # for which the combined maternal/fetal BW at GD 20 most closely matches % the maternal BW in Table 56 (Exxon, 1991) at GD 20. p2f2b=[]; % empty results array for n=l:3; BWINIT=BWs(n); DOSEF=doses(n); NUMFET=nfet(n); % Assign group input values start @nocallback sscheck = _cv(GSTART*24)/_cv((GSTART-l)*24) -1 % check for periodicity/SS @ GSTART, should be ~ 0 % Below appends inputs and results to array p2f2b = [p2f2b; [BWINIT, DOSEF, NUMFET, _bw(TSTOP-24), (_aucbb(find(_t==TSTOP))- _aucbb(find(_t==gdosestart)))/gesthr]]; % AUC/time = avg cone %plot(_t/24,_cv) end Page 28 of 48 ------- p2f2b NMP_99_SD.m % Simulations of THORNTON FEED STUDY %ESTIMATED ASSUMING A 12 HR "INFUSION" RATE FOR AN ORAL DOSE. use ratparam use preg_rat_params prepare @clear @all % T DAYS AUCBB CV load @file='NMP_99_SD.csv' @format=ascii @separator=comma dat=NMP_99_SD; GDDAYS=0.01; TSTART=0.01; CINT=0.1; res=[]; GSTART=7; BWINIT=mean(dat(g,l))/1000; TSTOP=(20+GSTART)*24; DOSEF=164; start @nocallback rng=find((_t/24)>=GSTART); [BWINIT, DOSEF, (AUCBB-_aucbb(rng(l)))/20, max(_cv(rng))] for g = l:length(dat) BWINIT=dat(g,l)/1000; TSTOP=(7+GSTART)*24; DOSEF=dat(g,2); start @nocallback DOSEF=dat(g,3); TSTOP=(14+GSTART)*24; continue @nocallback DOSEF=dat(g,4); TSTOP=(20+GSTART)*24; continue @nocallback rng=find((_t/24)>=GSTART); res = [res; [g, dat(g,l), (AUCBB-_aucbb(rng(l)))/20, max(_cv(rng))]] end plot((_t/24) - GSTART,_cv,'SD_preg_99.aps') dat=[dat,res] save dat @file='NMP_99_SD_res.csv' @format=ascii @separator=comma NMP_99_Wistar.m % Simulations of THORNTON FEED STUY %ESTIMATED ASSUMING A 12 HR "INFUSION" RATE FOR AN ORAL DOSE. use ratparam use preg_rat_params prepare @clear @all % T DAYS AUCBB CV load @file='NMP_99_Wistar.csv' @format=ascii @separator=comma dat=NMP_99_Wistar; GDDAYS=0.01; TSTART=0.01; CINT=0.1; res=[]; GSTART=7; Page 29 of 48 ------- BWINIT=mean(dat(g,l))/1000; TSTOP=(20+GSTART)*24; DOSEF=74; start @nocallback rng=find((_t/24)>=GSTART); [BWINIT, DOSEF, (AUCBB-_aucbb(rng(l)))/20, max(_cv(rng))] for g = l:length(dat) BWINIT=dat(g,l)/1000; TSTOP=(7+GSTART)*24; DOSEF=dat(g,2); start @nocallback DOSEF=dat(g,3); TSTOP=(14+GSTART)*24; continue @nocallback DOSEF=dat(g,4); TSTOP=(20+GSTART)*24; continue @nocallback rng=find((_t/24)>=GSTART); res = [res; [g, dat(g,l), (AUCBB-_aucbb(rng(l)))/20, max(_cv(rng))]] end plot(_t/24 - GSTART,_cv,'Wistar_preg_99.aps') dat=[dat,res] save dat @file='NMP_99_Wistar_res.csv' @format=ascii @separator=comma % results for PO males, using observed BW at week 17 and TWA achieved doses bws=[400.6 399.2 403.7]/1000; doses=[48.7 155.8 487.0]; TSTOP=GSTART*24; r2=[]; for g=l:3 BWINIT=bws(g); DOSEF=doses(g); start @nocallback r2 = [r2; [BW DOSEF (AUCBB-_aucbb(find(_t==(TSTOP-24))))]]; plot(_t/24 - GSTART,_cv) end r2 r3=[]; for DOSEF=[50, 160, 450] rr=DOSEF; for BWINIT=(2:6)/10 start @nocallback rr=[rr, (AUCBB-_aucbb(find(_t==(TSTOP-24))))]; end r3 = [r3;rr] end pl°t(_t,_cv) Page 30 of 48 ------- 2 Human NMP PBPK Model Code PROGRAM NMPhumPG.csl ! PBPK MODEL FOR N-METHYL PYRROLIDONE in pregnant women ! T.S. POET, P HINDERLITER. CHEMICAL DOSIMETRY GROUP, PNNL, RICHLAND, WA ! First Created 8.8.08 ! FINAL REPORT FROM INITIAL rat MODEL DEVELOPMENT SUBMITTED 9.02 ! 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-LIMITED (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:BLOOD PART. COEFF. RAT = 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 VALUES in cmd file ! Other parameters changed nominally to harmonize with fetal IPA model of ! Gentry et al. Regu Tox Pharm 36:51-68, 2002 ! Gentry model notes: ! -Coding for pregnancy is from MeHgFat.CSL with some minor changes ! -Physiological parameters are from MeHgFat.CSL (ajusted as needed) ! -Non-pregnant mammary tissue and uterine volume is from ICRP ! -Non-pregnant mammary tissue and uterine blood flows are based on the ! - ratios of mammary and uterine tissue volumes to rapidly perfused ! - tissue volume and blood flow to rapidly perfused tissue where rapidly ! - perfused tissue includes liver, lung, etc. ! - ((VMamC/VRapC)*QRapC) and ((VUtrC/VRapC)*QRapC) ! -Data used to fit curve for growing rapidly perfused tissue in ! - MeHgFat.CSL was refit separately to fit curves for growing uterus ! - and mammary tissue in this model ! -Body weight and cardiac output are calculated as the initial values ! - plus the change in the growing compartments ! -Increase in blood flow to fat, mammary tissue, and uterus are modeled ! - as being proportional to the increase in volume in those compartments ! - based on the data in Thoresen and Wesche, 1988 (uterus and mammary ! - tissue) Page 31 of 48 ------- ! Further updates by Paul Schlosser, US EPA in Aug 2013, Sept 2014, Apr-Dec 2020 INITIAL table reslvl, 1, 2881 / 2881*0.0, 2881*0.0 / table pvlf, 1,3/ 0.0, 0.5, 1.0, 4.78e-4, 4.78e-4, 2.05e-3 / ! PVLF returns the estimated permeability from NMP solutions estimated for 50% NMP (4.78e-4) ! when the argument (weight fraction, WF) is between 0 and 0.5, and linear interpolation to ! the value measured for neat NMP (2.05e-3) for WF between 0.5 and 1.0 ! Human Total Pulmonary Ventilation Rate (L/hr for 1 kg animal) CONSTANT QPC = 27.75 ! Human Blood Flows (fraction of cardiac output) CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT QCC = 12.9 QFatC = 0.052 QLivC = 0.227 QMamC = 0.027 QRapC = 0.325 QSkC = 0.058 QUtrC = 0.0062 Cardiac output (L/hr for 1 kg animal) Fat (non-pregnant female) Liver Mammary tissue (non-pregnant female) Rapidly perfused Skin Uterus (non-pregnant female) ! Permeability-Area Product (L/hr) CONSTANT PAFC = 0.01 ! Diffusion on fetal side of placenta from Gentry ! Human Tissue Volumes (fraction of body weight) CONSTANT BWInit = 67.8 ! Pre-pregnancy body weight (kg) CONSTANT VAIvC = 0.0079 ! Alveolar blood CONSTANT VBLC=0.06 CONSTANT VFatC = 0.273 ! Fat (non-pregnant female) CONSTANT VLivC = 0.026 ! Liver CONSTANT VMamC = 0.0062 ! Mammary tissue (non-pregnant female) CONSTANT VRapC = 0.1044 ! Rapidly perfused ! CONSTANT VSIwC ! Slowly perfused is calculated below CONSTANT VUtrC = 0.0014 ! Uterus (non-pregnant female) CONSTANT VSKC=0.19 ! Skin ! Human Dermal Exposure Parameters CONSTANT PV = 31.0 ! PERMEABILITYT CONSTANT (CM/HR) FOR VAPOR ! CONSTANT PVL = 0.0 ! PERMEABILITYT CONSTANT (CM/HR) FOR liquid CONSTANT FAD = 0.0 ! FRACTION ABSORBED - FROM BADER ET AL, CALCULATE FROM AMNT REMAINING ON GAUZE ! FOR PARENT MODEL, SKIN COMPARTMENT IS ONLY DEFINED AS DOSED SKIN CONSTANT SAL = 0.01 ! SURFACE AREA EXPOSED to liquid, SQ.CM Page 32 of 48 ------- CONSTANT SAvc = 0.25 ! fraction SURFACE AREA EXPOSED to gas/vapor, SQ.CM Constant amask = 0.03 ! Fraction surface area covered by a face mask CONSTANT HT=170.0 ! height (or length) of reference man TSA = 71.81 *(BWinit**0.425)*(HT**0.725) !for humans, DuBois and DuBois, 1916, as reported in Reference Man SAv = SAVC*TSA ! SURFACE AREA EXPOSED to gas/vapor, SQ.CM VSKIC = VSKC*SAI/TSA QSKIC = QSKC*SAI/TSA VSKvC = VSKC*SAv/TSA QSKvC = QSKC*SAv/TSA ! Slowly perfused (defined as balance of tissues and flows) VSIwC = 0.91 - (VFatC + VLivC + VMamC + VRapC + VUtrC + VSKvC + VSKIC) ! NOTE: 0.91 IS APPROX WHOLE BODY LESS BONE VSLwC5=0.91 - (VFatC + VLivC + VRapC) QSIwC = 1.0 - (QFatC + QLivC + QMamC + QRapC + QUtrC + QSKvC + QSKIC) QSIwC5 = 1.0 - (QFatC + QLivC + QRapC) ! Molecular Weights CONSTANT MW=99.13 ! MOL. WT. NMP, MG/MMOL CONSTANT MW1= 116.14 ! MOL. WT. 5-HNP, MG/MMOL Stoch = MW1/MW ! Stoichiometric multiplier ! Human NMP/Blood Partition Coefficients ! EXPERIMENTALLY MEASURED RATVALUES CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT CONSTANT PB = 450.0 Blood/air PFat = 0.61 Fat PLiv = 1.00 Liver PMam = 1.0 Mammary tissue, estimated from liver PPIa = 0.31 Placenta PRap = 1.0 Rapidly perfused tissue, liver PSIw = 0.30 Slowly perfused tissue, muscle PUtr = 0.34 Uterus PSKA = 44.5 use (blood/air)*(rat skin:liquid)/(human blood:liquid) PSKL = 0.42 MEASURED SKIN;LIQUID (rat) pskb = 0.099 (rat skin:liquid)/(human blood:liquid) PLU= 0.1 LUNG:BLOOD ! METABOLIC RATE CONSTANTS ! **THESE ARE FROM PAYAN ET AL ! NMP TO 5HNP CONSTANT Afl = 0.0112 ! AFFINITY CONSTANT, l/MG CONSTANT VK1C = 0.4663 ! Vmaxc/Km, l/(hr * BWA0.75 ) Page 33 of 48 ------- ! Human 5HNMP volume of distribution CONSTANT VOD5Hc = 0.3 ! VOLUME-OF-DISTRIBUTION VOD5H = VOD5Hc*BWinit ! No fetal compartment for metabolite, NMP is considered the active moiety ! 5HNPTO OTHER METABS ! CONSTANT KM2=22.8 ! MICHAELIS CONSTANT, MG/L ! CONSTANT VMAX2C=1.0 ! MAX. ENZ. ACT., MG/HR/L CONSTANT VK2C=0.0326 ! VMAX2C/KM2, since clearance ~ liner l/(hr*kgA0.75) ! Human Uptake and Clearance Parameters ! URINARY ELIMINATION OF 5-HNMP - CLEARED FROM BLOOD ! note first order rate commented out, saturable fits better CONSTANT KAS=5.0 CONSTANT KME=3.83 ! First-order constant for 5HNMP in urine (L/hr) CONSTANT KUMNE=0.182 ! First-order CONSTANT FOR NMP IN URINE (L/hr) ! Initialize Human Concentrations in Tissues (mg/L) CONSTANT ICArt = 0.0 CONSTANT ICFat = 0.0 CONSTANT ICLiv = 0.0 CONSTANT ICRap = 0.0 CONSTANT ICSkn = 0.0 CONSTANT ICSIw = 0.0 ! Blood ! Fat ! Liver ! Rapidly perfused ! Skin ! Slowly perfused ICMam = ICSIw ! Mammary tissue ICUtr = ICRap ! Uterus ! Dosing Parameters CONSTANT Concppm = 0.0 CONSTANT CONCMGM = 0.0 CONSTANT IVDose = 0.0 CONSTANT PDose = 0.0 CONSTANT PDrink = 0.0 CONSTANT TChng = 24.0 CONSTANT DaysWk = 5.0 CONSTANT TMax = 24.0 CONSTANT s2=0.0 ! INHALATION ON CONSTANT p2=3.0 ! INHALATION EXPOSURE CONSTANT S3=3.16 ! INHALATION RESUME (HANOVER STUDY and other scenarios) CONSTANT P3=3.0 ! SECOND DAILY EXPOSURE PERIOD logical on3, on4, on5 ! Set to zero to turn off 2nd daily pulse; Inhaled concentration (ppm) Inhaled concentration (mg/m3) IV dose (mg/kg) Oral dose (mg/kg) Drinking water dose (mg/kg/day) Length inh. exposure or IV inj.(hrs) Number of exposure days per week Maximum time for exposures Page 34 of 48 ------- CONSTANT s4=7.0 ! Third daily exposure start, period assumed = P3 constant s5=11.0 ! Fourth daily exposure start, period assumed = p3 constant on3=0 ! Set to one to turn on 2nd daily pulse; constant on4=0 ! Set to one to turn on 3rd daily pulse; constant on5=0 ! Set to one to turn on 3rd daily pulse; constant fullweek =168.0 ! hours in a full week hrsweek = 24.0*DaysWk ! h/week in workplace ! STARTDS IS ADDED TO TCHNG TO ALLOW FOR DOSING THAT DOES NOT START AT T=0 ! INITIAL EXPOSURE CONDITIONS ! DERMAL CONSTANT CONCL = 0.0 constant srate = 0.0 CONSTANT VLIQ0 = 1.0e-99 CONSTANT DENSITY=1.02e6 CONSTANT RESID=0.0 constant BRUSH = 0.0 CONC OF NMP IN LIQUID, MG/L mg/hr delivered to skin by spray application INITIAL VOLUME APPLIED, L Density (mg/L) @ 40C, ~ skin temperature AMOUNT STICKING TO EXPOSURE SYSTEM, MG Set to 1.0 for brush/liquid exposure DDN = (CONCL - 1.0)*VLIQ0*FAD ! Subtract 1 mg/L, ~ 1 ppm, from initial conc. to avoid VLIQ -> 0 WF0 = (CONCL -1.0)*FAD/DENSITY ! Initial weigh fraction in liquid AH20 = (DENSITY+1.0-CONCL)*VLIQ0 ! ... and add 1 ppm to H20. ! Note, for application of 100% NMP, it is not possible for CSURF to drop below 100%. ! 100% NMP is not diluted in anything, so the "solution" can't become less dilute. ! The volume (VLIQ) would actually decrease until it's all absorbed. ! Unless the experiment runs long enough for 100% absorption, treat VLIQ as ! extremely large, ~ 10A9, for 100% NMP. ! But check that you don't predict more absorption than was actually applied! ! 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) ! Exposure Conditions Based on User Defined Initial Amounts of Chemical (mg) IF (concppm.EQ.0.0) THEN concmg=concmgm/1000.0 ! Convert MG/M3 to mg/L ELSE CONCmg = CONCppm*MW/24451. ! Convert ppm to mg/Liter! ENDIF ! Simulation Control Parameters CONSTANT StartDs = 0.0 ! Time first dose is given (hrs) CONSTANT TStop = 6480.0 ! Run simulation for about 9 months CONSTANT ClntC = 0.1 CONSTANT GDstart = 0.0 ! Gestation day on which simulation starts ! Scaled Human Pulmonary Ventilation Rate (L/hr) Page 35 of 48 ------- QP = QPC * (BWInit**0.75) QAIv = 0.67 * QP ! Scaled Human Tissue Volumes (L) VAIv = VAIvC * BWInit VFatgO = BWInit*0.09*exp(-12.90995862) ! Fat weight growth term at start of pregnancy (gO) VFatl = BWInit*VFatC + VFatgO ! Total fat weight at gO VFetl = 3.50 * (exp(-16.081)+ exp(-140.178)) ! Fetal weight function value at gO VMamgO = BWInit*0.0065*exp(-7.444868477) ! Mammary weight growth term at gO VMaml = BWInit*VMamC + VMamgO ! Total mammary weight at gO VPIal = 0.85*exp(-9.434) ! Placenta weight function value at gO VUtrgO = BWInit*0.02*exp(-4.715669973) ! Uterus weight growth term at gO VUtrl = BWInit*VUtrC + VUtrgO ! Total uterus weight at gO VLiv = VLivC * BWInit VRap = VRapC * BWInit VSKI = VSKIC * BWinit VSKv = VSKvC * BWinit VBL= VBLC * BWINIT VSIw = VSIwC * BWInit BWO = BWInit + VFatgO + VMamgO + VUtrgO + VFetl + VPLal ! Scaled Human Blood Flows (L/hr) QCInit = QCC * (BW0**0.75) QFatl = QFatC * QCInit QLiv = QLivC * QCInit QMaml = QMamC * QCInit QPIal = 58.5 * VPIal ! value for 'days'=0 per calculation below QRap = QRapC * QCInit QSIw = (QSIwC * QCInit) - QPIal QUtrl = QUtrC * QCInit QSkl = QSKIC * QCInit QSkv = QSKvC * QCInit ! Scaled Human Metabolism Parameters VK1 = VK1C * (BW0**0.75) VK2 = VK2C * (BW0**0.75) ! Initialize Human NMP Amounts in Tissues IA Art = ICArt * VAIv lAFat = ICFat * VFatl lALiv = ICLiv * VLiv lAMam = ICMam * VMaml lARap = ICRap * VRap lASkl = ICSkn * VSKI Page 36 of 48 ------- lASkv = ICSkn * VSKv lASIw = ICSIw * VSIw lAUtr = ICUtr * VUtrl InitTot = lAArt + lAFat + lALiv + lAMam + lARap + lASkl + lASkv + lASIw + lAUtr ! Initialize Starting Values BW = BWInit Drink = (PDrink * BWO) / 24.0! Drinking water dose (mg/hr) CINT = ClntC IV = 0.0 DayExp = 1.0 Clnh = 0.0 CONSTANT FRACIN = 0.97 ! 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% ! Convert oral dose from ug/kg to umoles ! Modify dose to account for fractional absorption ODOSEl= PDOSE * BWO * FRACOR ! mg DZONE = 1.0 ! Start with dermal and fixed cone inhalation exposure on schedule offd.at.p2 schedule OND2.at.24.0 ! With the following three schedules it is assumed the length of use is the same ! for all three, set by p3. if (on3) schedule OND3.at.s3 if (on4) schedule ond3.at.s4 if (on5) schedule ond3.at.s5 END ! End of Initial DYNAMIC ALGORITHM IALG = 2 ! Gear stiff method DISCRETE DoseOn ! Start dosing INTERVAL Doselnt = 24.0 ! Interval to repeat dosing SCHEDULE DoseOff .AT. T + TChng IF ((T.GE.StartDs) .AND. (T.LT.TMax)) THEN IF (T.LE.(StartDs+TChng)) THEN IF (IVDose.GT.0.0) CINT = MIN(ClntC, (TChng/10.0)) IV = (IVDose*BW) / TChng ! Rate of intravenous dosing (mg/hr) ENDIF Page 37 of 48 ------- ENDIF END ! DoseOn DISCRETE DoseOff Clnh = 0.0 CI NT = ClntC IV = 0.0 END discrete OND2 DZONE=1.0 SCHEDULE OND2.AT.(T+24.0) SCHEDULE OFFD.AT.(T+P2) END discrete OND3 DZONE=1.0 SCHEDULE OND3.AT.(T+24.0) SCHEDULE OFFD.AT.(T+P3) END !EXPOSURE CONTROL DISCRETE OFFD DZONE=0.0 ! TURN OFF DERMAL & FIXED CONC INHALATION END DERIVATIVE Hours = T Minutes = T* 60.0 Days = T / 24.0 + GDstart Gtime = T + GDstart*24.0 ! Volume of human fat (L) VFat = BWInit*(VFatC+(0.09*exp(-12.90995862*exp(-0.000797*Gtime)))) ! Volume of human fetus (L) VFet = 3.50 * (exp(-16.081*exp(-5.67e-4*Gtime))+ exp(-140.178*exp(-7.01e-4*Gtime))) ! Volume of human mammary tissue (L) VMam = BWInit*(VMamC+(0.0065*exp(-7.444868477*exp(-0.000678*Gtime)))) ! Volume of human placenta (L) VPIa = 0.85*exp(-9.434*exp(-5.23e-4*Gtime)) Page 38 of 48 ------- ! Volume of human uterus (L) VUtr = BWInit*(VUtrC+(0.02*exp(-4.715669973*exp(-0.000376*Gtime)))) ! Increase in human body weight (kg) ! BW = BWInit + (VFat - VFatl) + VFet + (VMam - VMaml) + VPIa + (VUtr - VUtrl) BW = BWO + (VFat - VFatl) + (VFet - VFetl) + (VMam - VMaml) + (VPIa - VPIal) + (VUtr - VUtrl) ! Scaled human alveolar ventilation (L/hr) QP = QPC * (BW**0.75) QAIv = 0.67 * QP ! Increase in human blood flows (L/hr) QFat = QFatl * (VFat/VFatl) QMam = QMaml * (VMam / VMaml) QUtr = QUtrl * (VUtr/VUtrl) ! Human Blood flow to placenta (L/hr) QPIa = 58.5 * VPIa ! Increased human cardiac output (L/hr) QC = QCInit + (QFat - QFatl) + (QMam - QMaml) + (QPIa - QPIal) + (QUtr - QUtrl) QSIw5 = Qc - (QFat + QLiv + QRap) VSIw5 = BW - (VFat + VLiv + VRap) ! Scaled permeability-area product PAF = PAFC * (VFet**0.75) ! HUMAN NMP MODEL ! Amount Exhaled (mg) RAExh = QAIv * CAIv AExh = INTEG(RAExh, 0.0) CI = concmg*czone + RESLVL(T) ! for a 5 day/wk exposure, change first pulse to pulse(0,7*24,5*24) ! for daily, pulse(0,le6,24) TORAL = ODOSE1 - AO ! AMT ABSORBED ORALLY, MG! RSTOM = -KAS*AO ! Change in stomach (umole/hr) RAO = KaS*AO ! Rate of absorption (-RSTOM) AO=ODOSEl+INTEG(Rstom,0.0) ! Amt in stomach (umole) ! Amount in Fat (mg) RAFat = QFat * (CArt - CVFat) Page 39 of 48 ------- AFat = INTEG(RAFat, lAFat) CFat = AFat/VFat CVFat = CFat / PFat ! Amount in Fetus (mg) RAFet = PAF * (CPIa - CFet) AFet = INTEG(RAFet, 0.0) CFet = AFet / VFet AUCCFet = INTEG(CFet, 0.0) ! Amount in Liver (mg) RALiv = (QLiv * (CArt - CVLiv)) + RAO + Drink - RAMetl ALiv = INTEG(RALiv, lALiv) CLiv = ALiv / VLiv CVLiv = CLiv/PLiv ! Amount Metabolised in Liver - Saturable (mg) RAMetl = VK1 * CVLiv / (1 + afl*CVLiv) AMetl = INTEG(RAMetl, 0.0) ! Amount in Mammary Tissue (mg) RAMam = QMam * (CArt - CVMam) AMam = INTEG(RAMam, lAMam) CMam = AMam / VMam CVMam = CMam / PMam ! Amount in Placenta (mg) RAPIa = (QPIa * (CArt - CVPIa)) + (PAF * (CFet - CPIa)) APIa = INTEG(RAPIa, 0.0) CPIa = APIa/VPIa CVPIa = CPIa / PPIa ! Amount in Rapidly Perfused Tissue (mg) RARap = QRap * (CArt - CVRap) ARap = INTEG(RARap, lARap) CRap = ARap / VRap CVRap = CRap / PRap ! ASKI = AMOUNT NMP IN liquid-exposed SKIN TISSUES (MG) AND DERMAL DOSING (from vapor) ! Liquid exposure when czone = 1, otherwise czone = 0. CI = air concentration czone = pulse(0.0,fullweek,hrsweek)*DZONE ! for a 5 day/wk exposure, use fullweek=7*24, hrsweek=5*24 (Dayswk=5) ! for a single day, fullweek=lel6, hrsweek=24 (Dayswk=l) PVLU=PVLF(WF) Page 40 of 48 ------- RADL = (PVLU*SAL/1000.0)*(CSURF - (CSKL/PSKL))*czone*BRUSH ! Net rate of delivery to "L" skin from liquid, when liquid is there ADLL = integ(RADL, 0.0) RADVL = (PV*SAL/1000.0)*(CI - (CSKL/PSKA))*(1.0-Czone*BRUSH) ! Net rate of delivery to "L" skin from air, when liquid not present ADVL = integ(RADVL, 0.0) ASURF = INTEG(-RADL, DDN) ! Amount in liquid. DDN is the initial amount. VUQ = (AH20 + ASURF)/DENSITY CSURF = ASURF/VLIQ WF = CSURF/DENSITY RASKL = QSKL*(CArt - CvSKL) + RADL + RADVL ! Rate of change in "L" skin compartment ASKL = INTEG(RASKL, 0.0) ! Amount in "L" skin CSKL = ASKL/VSKL ! Concentration in "L" skin CvSKL = CSKL/PSKB ! Concentration in venous blood exiting "L" skin ! ASKv = AMOUNT NMP IN vapor-exposed SKIN TISSUES (MG) AND DERMAL DOSING (from vapor); ! "SKv" (vapor-only-exposed) skin compartment. CI = air concentration RADVv = (PV*SAv/1000.0)*(CI*(1.0 - AMASK/SAVC) - (CSKv/PSKA)) ! Net rate of transfer from air to skin ! In above, CI is reduced in proportion to mask fractional coverage (AMASK), so *average* ! concentration of air over exposed skin is reduced from CI by AMASK/SAVC. ! If the concentration inside the mask is 10% of exposure and the surface area fraction of the ! face (covered by the mask) is 'mask' = 0.03, and SAVC is the surface area fraction otherwise ! exposed, then the average concentration of vapor-exposed skin (weighted by surface area) is: ! [(SA fully exposed)*CI + (SA of mask)*10%*CI]/SAVC = ! [(SAVC - mask)*CI + mask*0.1*CI]/SAVC = [1 - 0.9*mask/SAVC]*CI ! = (1 - AMASK/SAVC)*CI, ! if AMASK = 0.9*mask; i.e., the mask effectively covers 90% of the face, reduces CI by AMASK/SAVC. ADVv = INTEG(RADVv,0.0) 1'AMT NMP ABSORBED DERMAL, MG' RASKv = QSKv*(CArt - CvSKv) + RADVv ! Rate of change in "V" skin ASKv = INTEG(RASKv, 0.0) ! Amount in "V" skin CSKv = ASKv/VSKv ! Concentration in "V" skin CvSKv = CSKv/PSKb ! Concentration in venous blood exiting "V" skin ! Amount in Slowly Perfused Tissue (mg) RASIw = QSIw * (CArt - CVSIw) ASIw = INTEG(RASIw, lASIw) CSIw = ASIw / VSIw CVSIw = CSIw / PSIw ! Amount in Uterus (mg) RAUtr = QUtr * (CArt - CVUtr) Page 41 of 48 ------- AUtr = INTEG(RAUtr, lAUtr) CUtr = AUtr / VUtr CVUtr = CUtr / PUtr ! BLOOD VENOUS ARTERIAL (c) CVEN = (QFAT*CVFat + QLIV*CVLiv + QMAM*CVMam + QPLA*CVPIa + QRap*CVRap + QSIw*CVSIw & + QUtr*CVUtr + QSKV*CVSKv + QSKL*CVSKL + IV) / QC lvtot= INTEG(IV, 0.0) ! Amount in Arterial Blood (mg) RAINH = QAIv*(CI*FRACIN - CAIv) RABId = RAINH + QC*(CVen-CArt) - RAUNP INhaltot = INTEG(RAINH, 0.0) ABId = INTEG(RABId, lAArt) CArt = ABId / VBL CAIv = CArt/ PB CAIvPPM = CAIv * 24450.0 / MW AUCCBId = INTEG(CArt, 0.0) ! Amount in Urine (mg) RAUNP = KUMNE*CART ! FIRST ORDER RATE OF LOSS (URINE AUNP = INTEG(RAUNP,0.0) ! HUMAN 5HNMP MODEL ! Amount in body (mg) RA5H = (RAMetl*STOCH) - RAMetMl - RAUHP A5H = INTEG(RA5H, 0.0) Cvenl = A5H / VOD5H ! Amount Metabolised [in Liver] - Saturable (mg) RAMetMl = VK2*Cvenl AMetMl = INTEG(RAMetMl, 0.0) ! Amount in Urine (mg) RAUHP = KME*Cvenl AUHP = INTEG(RAUHP,0.0) ! CHECK MASS BALANCE INTOT=INTEG((QAIv*CI*FRACIN), 0.0) TDose = INTOT + AO + InitTot +TORAL +ADLL +ADVL +ADvV NMPTOT =ABId +AFat +AFet +ALiv +AMam +APIa +ARap +ASkl +ASkv +ASIw +AUtr +AExh +AUnp +AMET1 MassBal = TDose/(NMPTOT+0.000000000001) Page 42 of 48 ------- TERMT(T.GT.TSTOP, 'Simulation Finished') END ! End of Derivative TERMINAL DAUCCBId = AUCCBId * 24.0 / TStop DAUCCFet = AUCCFet * 24.0 / TStop END END ! End of Dynamic END ! End of Program % 2020 script to run NMP PBPK analysis for residential exposures, female users exist cont if ~ans cont=0 end if cont cd .. cont=0 end cont=l % Files appearing in 'load' statements below should be in sub-folder set by 'cd' below (~ line 23) sclist=["Paint_Remover_l"; "Paint_Remover_2"; "Adhesives_l"; "Adhesives_2"]; % list of scenario/tab names fname=" Residential_Dec2020.xls" res=[]; use human_params use human_avg_params TSTOP=24; CINTC=0.01; BWINIT=74; VLIQ0=le6; prepare @clear T CVEN AUCCBLD CI CSURF CZONE RESLVL CART ASURF AUCCBLD % Fixed parameters for residential exposure scenarios AMASK=0; S2=0; ON3=l; % 2 daily exposures % PVLF(3)=4.78e-4 cd 'resid_female' load rt @file='Resid2020_time.csv' @format=ascii @separator=comma % time array of air concentrations, assuming all are the same, use the 1st one % Paint_Remover_l sc=l; % scenario # load data @file=Paint_Remover_lb.csv @format=ascii @separator=comma; RESLVL=[data(:,l)/1000;rt]; aWF=0.6; P2=4.5/60; ON3=l; S3=45/60; P3=5/60; CONCL=aWF*DENSITY; % CONCL is NMP concentration in liquid mg/L Page 43 of 48 ------- BRUSH=1; salO = 445; % surface area of hands exposed/no gloves cvs = []; for BWINIT= [74 65.9] HT=170.0 % height (or length) of reference man start @nocallback % Run to calculate TSA for BWINIT aglove=890/TSA; % fraction of surface area covered by gloves aliq=salO/TSA; % fraction of surface area covered by liquid % Simulations for user for gloves = [1 0] rexp = [sc aWF BWINIT gloves] SAL=salO/(l+4*gloves); % gloves have PF = 5 SAVC=0.25-gloves*aglove-(l-gloves)*aliq; for GDSTART= [0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end res=[res; rexp]; cil=_ci; cvs=[cvs,_cven]; end end % Simulations for bystander adult female BWINIT=74; BRUSH=0; SAL=0.01; SAVC=0.25; rexp=[sc 0 BWINIT 0]; for GDSTART = [0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end ci2=_ci; cvs=[cvs,_cven]; res=[res; rexp] % Simulations for rest-of-house adult female RESLVL=[data(:,2)/1000;rt]; rexp=[sc 0 BWINIT 0]; for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end ci3=_ci; cvs=[cvs,_cven]; res=[res; rexp] % Simulations for rest-of-house child BWINIT=18.6; HT=105.7; GDSTART=0; rexp=[sc 0 BWINIT 0]; start @nocallback res = [res; [rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE), NaN, NaN, NaN]]; plot(_t,cil* 1000,_t,ci2* 1000,_t,ci3* 1000,'residential_ci.aps') plot(_t,[cvs(:,[5 2 6])],'residential_cv.aps') Page 44 of 48 ------- % Paint_Remover_2 sc=2; % scenario # load data @file=Paint_Remover_2b.csv @format=ascii @separator=comma; RESLVL=[data(:,l)/1000;rt]; aWF=0.6; P2=18/60; S3=84/60; P3=18/60; ON4=l; S4=228/60; ON5=l; S5=312/60; % Turning on 3rd and 4th daily exposure CONCL=aWF*DENSITY; % CONCL is NMP concentration in liquid mg/L BRUSH=1; salO = 445; % surface area of hands exposed/no gloves cvs = []; for BWINIT= [74 65.9] HT=170.0 % height (or length) of reference man start @nocallback % Run to calculate TSA for BWINIT aglove=890/TSA; % fraction of surface area covered by gloves aliq=salO/TSA; % fraction of surface area covered by liquid % Simulations for user for gloves = [1 0] rexp = [sc aWF BWINIT gloves] SAL=salO/(l+4*gloves); % gloves have PF = 5 SAVC=0.25-gloves*aglove-(l-gloves)*aliq; for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end res=[res; rexp]; cil=_ci; cvs=[cvs,_cven]; end end % Simulations for bystander adult female BWINIT=74; BRUSH=0; SAL=0.01; SAVC=0.25; rexp=[sc 0 BWINIT 0]; for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end ci2=_ci; cvs=[cvs,_cven]; res=[res; rexp] % Simulations for rest-of-house adult female RESLVL=[data(:,2)/1000;rt]; rexp=[sc 0 BWINIT 0]; for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; Page 45 of 48 ------- end ci3=_ci; cvs=[cvs,_cven]; res=[res; rexp] % Simulations for rest-of-house child BWINIT=18.6; HT=105.7; GDSTART=0; rexp=[sc 0 BWINITO]; start @nocallback res=[res; [rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE), NaN, NaN, NaN]]; plot(_t,cil* 1000,_t,ci2* 1000,_t,ci3*1000,'residential_ci.aps') plot(_t,[cvs(:,[5 2 6])],'residential_cv.aps') % Turning off 2nd, 3rd, and 4th dermal exposures: ON3=0; ON4=0; ON5=0; % Third scenario, Adhesives 1 sc=3; % scenario # load data @file=Adhesives_lb.csv @format=ascii @separator=comma; RESLVL=[data(:,l)/1000;rt]; aWF=0.85; P2=4.25/60; CONCL=aWF*DENSITY; % CONCL is NMP concentration in liquid mg/L BRUSH=1; salO = 445; % surface area of hands exposed/no gloves for BWINIT= [74 65.9] cvs = []; cil = []; HT=170.0 % height (or length) of reference man start @nocallback % Run to calculate TSA for BWINIT aglove=890/TSA; % fraction of surface area covered by gloves aliq=salO/TSA; % fraction of surface area covered by liquid % Simulations for user for gloves = [1 0] rexp = [sc aWF BWINIT gloves] SAL=salO/(l+4*gloves); % gloves have PF = 5 SAVC=0.25-gloves*aglove-(l-gloves)*aliq; for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end res=[res; rexp]; cil=_ci; cvs=[cvs,_cven]; end end % Simulations for bystander adult female BWINIT=74; BRUSH=0; SAL=0.01; SAVC=0.25; rexp=[sc 0 BWINITO]; Page 46 of 48 ------- for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end res=[res; rexp] % Simulations for bystander child BWINIT=18.6; HT=105.7; GDSTART=0; rexp=[sc 0 BWINITO]; start @nocallback res=[res; [rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE), NaN, NaN, NaN]]; plot(_t,cil* 1000,_t,_ci* 1000,_t,_czone,'residential_ci.aps') plot(_t,[cvs(:,[2 l]),_cven],'residential_cv.aps') % Fourth scenario, Adhesives 2 sc=4; % scenario # load data @file=Adhesives_2b.csv @format=ascii @separator=comma; RESLVL=[data(:,l)/1000;rt]; aWF=0.85; P2=60/60; CONCL=aWF*DENSITY; % CONCL is NMP concentration in liquid mg/L BRUSH=1; salO = 445; % surface area of hands exposed/no gloves for BWINIT= [74 65.9] cvs = []; cil = []; HT=170.0 % height (or length) of reference man start @nocallback % Run to calculate TSA for BWINIT aglove=890/TSA; % fraction of surface area covered by gloves aliq=salO/TSA; % fraction of surface area covered by liquid % Simulations for user for gloves = [1 0] rexp = [sc aWF BWINIT gloves] SAL=salO/(l+4*gloves); % gloves have PF = 5 SAVC=0.25-gloves*aglove-(l-gloves)*aliq; for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end res=[res; rexp]; cil=_ci; cvs=[cvs,_cven]; end end % Simulations for bystander adult female BWINIT=74; BRUSH=0; SAL=0.01; SAVC=0.25; rexp=[sc 0 BWINITO]; Page 47 of 48 ------- for GDSTART=[0 8]*30 % Gestation day on which simulations start start @nocallback rexp=[rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE)]; end res=[res; rexp] % Simulations for bystander child BWINIT=18.6; HT=105.7; GDSTART=0; rexp=[sc 0 BWINITO]; start @nocallback res=[res; [rexp, AUCCBLD, max(_cven), (1 - (AEXH + AUNP + AMETl)/TDOSE), NaN, NaN, NaN]]; plot(_t,cil*1000,_t,_ci*1000,_t,_czone,'residential_ci.aps') plot(_t,[cvs(:,[2 l]),_cven],'residential_cv.aps') xlsWrite(fname, "results", "A3:J30",res) save res @file=Residential2020.csv @format=ascii @separator=comma cont=0 cd .. 3 References Poet. TS; Kirman. ( ier. M; van Thriel. C; Gargas. ML; Hinderliter. PM. (2010). Quantitative risk analysis for N-methyl pyrrolidone using physiologically based pharmacokinetic and benchmark dose modeling. Toxicol Sci 113: 468-482. http://dx.doi.ore/10.1093/toxsci/kfp264. (2013). TSCA workplan chemical risk assessment n-Methylpyrrolidone: Paint stripping use CASRN: 872-50-4. Draft. Washington, DC: Office of Pollution Prevention and Toxics, US Environmental Protection Agency. U.S. EPA. (2018). An umbrella Quality Assurance Project Plan (QAPP) for PBPK models. Research Triangle Park: U.S. Environmental Protection Agency. Page 48 of 48 ------- |