Preface to “A PK/PBPK MODEL QUALITY ASSURANCE ASSESSMENT FOR THE 

TSCA WORKPLAN RISK ASSESSMENT OF N-Methylpyrrolidone”

Prepared by Paul Schlosser, Ph.D.

U.S. Environmental Protection Agency

National Center for Environmental Assessment

Poet et al. (2010) developed a PBPK model to reduce uncertainty associated with extrapolating findings 

from animal toxicity studies to humans. These authors initially developed the model for adult nonpregnant rats and then extrapolated it to pregnancy. The U.S. EPA regularly reviews not only the primary 

publications describing PBPK models, but performs a quality assurance (QA) review, as described by 

(McLanahan et al., 2012). Since the model as described by Poet et al. (2010) appeared to be of sufficient 

scientific quality, the model code was obtained from the principle author, Dr. Torka Poet. The QA 

process involves checking that the published tables and figures can be reproduced, that the parameters 

used in the code match those listed in the publication (or at a minimum, are consistent between model 

simulations and appropriate for the chemical and animal species and/or humans being simulated), and that 

the equations in the code are correct and match those listed or indicated in the published paper. This 

review has been conducted by members of the U.S. EPA National Center for Environmental Assessment 

(NCEA) Pharmacokinetics Workgroup (PKWG), with technical support through an external contract. 

The contractor’s report and further details from the PKWG NMP team lead (Paul Schlosser) follow.

The initial QA review conducted in the fall of 2012 found several code errors and parameter 

inconsistencies in the model and the EPA was not able to reproduce all of the figures in Poet et al. (2010) 

as well as should be possible. At that point the model was not considered to be of sufficient quality for 

use in a risk assessment. Subsequently Dr. Torka Poet corrected the model errors originally found by the 

U.S. EPA and created a set of scripts to aid in reproducing her results (for the NMP Producers Group). 

As these changes substantially changed some of the model predictions, the revised model results were 

described in a report that was submitted to the U.S. EPA in April, 2013.

Overall quality: The U.S. EPA then treated this revised model report (Poet, 2013) and code as a new 

publication and again conducted a QA review. Several more coding and parameter errors were found, as 

described below in this preface, in the contractor’s report which follows, and in EPA’s appendix to that 

report. In this case, however, correcting the errors caused only modest changes in the model predictions 

(fits to data) used to calibrate the model and determine its suitability for risk prediction, subsequent to the 

changes and corrections described here, in the QA report, and appendix. Since the fits of the model to the 

various data sets evaluated appears adequate and the parameter values are appropriate and consistent, the 

model is now deemed to be of sufficient quality for use in this risk assessment.

Dermal absorption of NMP vapor: One parameter inconsistency that results in differences in predictions 

for human exposure scenarios is the assumed surface area (SA) of skin through which vapor can be 

absorbed. The human model calibration for inhalation was conducted by Poet (2013) with a SA of 6700 

cm2, presumed to be face, neck, lower arms, and hands, through which vapor was absorbed, accounting 

for about 45% of the uptake when exposure is by inhalation only. Since these skin areas would also be 

exposed to vapors for individuals working with NMP, the model code and parameter files were revised to 
include this route and SA as base assumptions for human exposures, which can occur simultaneous with 

dermal liquid absorption.

Oral absorption kinetics in rats: While the oral exposure is not of concern for human workplace and 

residential scenarios being evaluated by OPPT, the rat PBPK model includes oral dosimetry and 

calibration to rat oral data was shown by Poet et al. (2010). In order to evaluate possible internal dose 

metrics for their ability to predict developmental effects, oral bioassay data for rats is also evaluated in the 

dose-response analysis. Hence the ability of the rat model to correctly predict internal doses after oral 

exposure is also important. However, since this calibration was not carried forward from Poet et al. 

(2010) to Poet (2013), it was not evaluated in the contractor’s report which follows. 

When the otherwise revised model was tested by the U.S. EPA for its ability to reproduce the oral 

absorption kinetics shown in Figure 5 or Poet et al. (2010) for rats, an error in the coding (revised version 

provided with Poet (2013)) gave a significant discrepancy between the predictions with the revised model 

and that figure. In particular, the total mass of NMP available for oral uptake was not reduced to reflect 

the oral bioavailability (FRACOR = 68%) reported by Poet et al. (2010) and instead the rate constant for 

absorption, KAS, was effectively reduced by this extent. Since any material deposited in the model’s 

stomach lumen compartment is eventually absorbed, irrespective of the value of KAS, the effective 

bioavailability was therefore erroneously treated as being 100%. When the code was corrected to reduce 

the mass deposited to the stomach lumen compartment to 68% and KAS also reduced to 0.92/h (68% of 

the value in the provided code, 1.36/h), and the incorrect multiplication of KAS and FRACOR removed 

from the code, fits to the plasma NMP data for rat oral exposures were of a similar quality to that shown 

in Figure 5 of Poet et al. (2010), first figure below. 

Fits to the corresponding data for urinary clearance of 5HNMP in the second plot below (not shown by 

Poet et al., 2010) are also considered adequate, given that the metabolite is not considered to be the 

proximate toxicant. That the NMP plasma levels (middle curve in first plot) observed by Ghantous 

(1995) for a dose of 57 mg/kg are roughly 50% of those observed by Midgley et al. (1992) for a 112 

mg/kg exposur while the 5HNMP levels observed by Ghantous (1995) were 80% of those reported by 

Midgley et al. (1992) suggests either an experimental discrepancy or a nonlinearity in 5HNMP clearance 

that is not well captured by the model. It should be noted that the model does describe well the urinary 

clearance of 5HNMP after a range of IV and inhalation exposures, as validated in the following QA 

report. Since the U.S. EPA is not using 5HNMP levels as an internal dose metric, this particular 

discrepancy in the oral data is not considered severe enough to preclude the PBPK model for use.
Revised PBPK Model Simulations vs. Data for Oral Gavage Exposures of NMP to Rats

Additional references (not included in following contractor’s report)

Ghantous, H. 1995. In Oral, Dermal, and Inhalation Pharmacokinetics and Disposition of [2-14 C] NMP 

in the Rat. Report for E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and 

Industrial Medicine, Wilmington, DE.

McLanahan, E.D., El-Masri, H.A., Sweeney, L.M., Kopylev, L.Y., Clewell, H.J., Wambaugh, J.F., 

Schlosser, P.M. 2012. Physiologically based pharmacokinetic model use in risk assessment--why being 

published is not enough. Toxicol Sci 126, 5-15.

Midgley, I., Hood, A. J., Chasseaud, L. F., Brindley, C. J., Baughman, S., and Allan, G. 1992. 

Percutaneous-absorption of co-administered N-methyl-2-[C-14]pyrrolidinone and 2-[C-14]pyrrolidinone 

in the rat. Food Chem. Toxicol. 30, 57–64.
A PK/PBPK MODEL QUALITY ASSURANCE ASSESSMENT FOR THE TSCA 

WORKPLAN RISK ASSESSMENT OF N-Methylpyrrolidone

(CAS RN 872-50-4)

Under Battelle Prime Contract EP-C-09-006:

Physiologically-Based Pharmacokinetic (PBPK) Modeling Technical Support

Work Assignment WA 4-01

Prepared By:

Michael H. Lumpkin, Ph.D., DABT

P. Robinan Gentry, Ph.D., DABT

ENVIRON International Corporation

Monroe, Louisiana

Prepared for:

Paul Schlosser, Ph.D.

Work Assignment Manager

U.S. Environmental Protection Agency

National Center for Environmental Assessment

Submitted through:

Rena Thomas

Battelle Memorial Institute

Prime Contractor Address

505 King Avenue

Columbus, OH 43201

September 11, 2013
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TABLE OF CONTENTS

1 QUALITY ASSURANCE ASSESSMENT.......................................................................... 2

2 QA OF NMP MODEL (POET ET AL. 2010)..................................................................... 3

2.1 QA of NMP Model Parameters............................................................................................ 3

2.2 QA and Modification of NMP Model Equations................................................................ 3

3 NMP MODEL OUTPUT ...................................................................................................... 4

4 CONCLUSIONS.................................................................................................................... 5

5 REFERENCES ...................................................................................................................... 6

APPENDIX A. Modified AcslXtreme CSL and M Files Used for the QA Assessment....... 16

APPENDIX B. ............................................................................................................................. 63

LIST OF TABLES

Table 1. Differences between NMP PBPK model parameter values found in the provided model computer 

code and Poet et al. (2010)............................................................................................................................7

LIST OF FIGURES

Figure 1. Reproduction of Wells and Digenis (1988) and Payan et al. (2002) IV NMP exposures: Plasma 

profiles..........................................................................................................................................................8

Figure 2. Reproduction of Payan et al. (2002) IV NMP exposures..............................................................9

Figure 3. Reproduction of Payan et al. (2003) dermal NMP exposure.......................................................10

Figure 4. Reproduction of Poet et al. (2010) inhalation NMP exposures: Blood profiles..........................11

Figure 5. Reproduction of Poet et al. (2010) inhalation NMP exposures: Urine profiles...........................12

Figure 6. Reproduction of Akesson and Paulsson (1997) inhalation NMP exposures...............................13

Figure 7. Reproduction of Akesson et al. (2004) dermal NMP exposures .................................................14

Figure 8. Comparison of Akesson and Paulsson (1997) dermal with inhalation NMP exposures.............15

1 QUALITY ASSURANCE ASSESSMENT

A quality assurance (QA) assessment was conducted for a modified physiologically based 

pharmacokinetic (PBPK) model for orally ingested, inhaled, or dermally absorbed n-methylpyrrolidone

(NMP) in rats and humans reported by Poet et al. (2010). The evaluation was conducted to insure that the 

model structure and parameter values presented by Poet et al. (2010) are accurately reflected in the 

computer code implementation. Changes to the model code that would more accurately represent the 

physiology/biology of NMP pharmacokinetics were discussed and implemented. Simulations of rat and 

human exposures that were presented by Poet (2013) were performed and shown here to demonstrate the 

ability of the current model code to replicate experimental observations. 
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2 QA OF NMP MODEL (POET ET AL. 2010)

The initial PBPK model computer code relied upon for the QA assessment was supplied by Battelle/ 

Pacific Northwest National Laboratories. The model code was written in the ACSL programming 

language and was modified/assessed using the acslXtreme software package (version 3.0.2.1, Aegis 

Technologies, Inc.). Separate code files were provided for the rat and human models.

2.1 QA of NMP Model Parameters

The NMP model parameter values in the provided model code were checked against the values published 

in Poet et al. (2010), as well as with Brown et al. (1997) for physiological values and Gentry et al. (2002) 

for pregnancy-related growth rates. Rat and human model parameter values were assigned in acsl 

command files (m files), which set parameter values (including exposure conditions), invoke simulation 

runs, and plot the resulting simulations. Several rat model parameter values included in the acsl model 

code were different from the values provided in Tables 1, 2, and 5 of Poet et al. (2010). Differences in rat 

model parameters included the molecular weight for the modeled metabolite, 5-hydroxy-N-methyl-2-

pyrrolidone (5-HNMP), fractional blood flow to the mammary glands, uterus, and skin, lung tissue 

volume, first order urinary elimination rate of 5-HNMP, and equilibrium tissue:blood partition 

coefficients for NMP in the lung and slowly-perfused lumped tissues compartments (Table 1). The 

reference for the rat tissue:blood partition coefficients for NMP used in the model code for the placenta 

(0.309) and for 5-HNMP for placenta and rest-of-body (1.07 and 0.73, respectively) were not provided in 

the model code or cannot be estimated based on the information provided in Table 5 of the Poet et al. 

(2010) paper. 

Similarly, the human model command files assigned parameter values that were different from published 

values for molecular weight for NMP, fractional blood flow to the skin and uterus, NMP vapor 

permeability constant, and fat:blood partition coefficient for 5-HNMP (Table 1). Additionally, source 

references for tissue:blood partition coefficient values for NMP in the placenta and rapidly-perfused 

tissues (0.31 and 0.94) and 5-HNMP in the rapidly- and slowly-perfused tissues and rest-of-body (6.5 and 

1.0) were not provided in the model code or cannot be determined based on the information provided in 

Table 5 of Poet et al. (2010) paper.

2.2 QA and Modification of NMP Model Equations

The equations used in the model code to calculate rates of change, amounts, concentrations, and areaunder-the-curve (concentration x time) of NMP and 5-HNMP absorption, distribution, metabolism, and 

elimination in blood and tissues were examined to assure that they accurately represented the model 

structure and relationships described by Poet et al. (2010). Poet et al. (2010) implemented equations for 

pregnancy-related changes in body weight, tissues volumes, pulmonary ventilation, and cardiac output 

used by Gentry et al. (2002). The only differences identified in the pregnancy-related growth equations 

were for the fetal compartment in rats. Gentry et al. (2002) described fetal growth as having three 

different phases beginning on the gestation days 0, 11, and 18, whereas the provided NMP model code 

implemented these changes in fetal growth rates on gestation days 0, 10, and 17. It was not clear if these 

differences in modeled fetal growth phases may be due to differences between the Poet et al. (2010) and 

Gentry et al. (2002) in defining time for onset of gestation in rats. 
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Two modifications were made by EPA staff to the code prior to the QA assessment and included:

a) Changing the body weight scaling exponent from 0.74 to 0.75 for all allometrically-scaled 

parameters, and 

b) Correcting the rate equation for dermal absorption of liquid NMP (RADL and RASL for rat and 

human models, respectively) of NMP from

RADL = ((KPL × SA / 1000) × CSURF) - (CSK/PSK)

to

RADL = (KPL × SA / 1000) × (CSURF - (CSK/PSK))

in the rat model, and from

RASL = ((PVL × SA/1000) × CSURF)-(CVSK/PSKL)

to

RASL = (PVL × SA/1000) × (CSURF-(CVSK/PSKL))

in the human model.

In addition, several errors in parameters for skin volumes (total body skin or exposed skin only) and 

equations calculating tissue-specific NMP concentrations in the human model were identified by the EPA 

WAM, Paul Schlosser, and were corrected. The corrections include selection of an exposure-specific skin 

volume to use in calculating NMP vapor absorption, introducing a term in the vapor absorption rate that 

accounts for evaporative NMP loss from the skin (after exposure cessation), corrections in calculating 

NMP concentration leaving the skin and entering the venous circulation, correction in the calculation of 

cardiac output and tissue volume of the slowly-perfused compartment by removing the skin volume term, 

and introduction of spray-on NMP dermal exposures. Also, the human model code was modified to 

remove discontinuities in placental blood flow at time zero (causing the model to crash) and fat, 

mammary, and uterine volumes. Pregnancy-related cardiac output and volume growth changes for 5-

HNMP in fat were not properly reflected in the slowly-perfused compartment. This resulted in a blood 

flow mismatch and an artificial loss of 5-HNMP. A detailed description of all of these changes is 

provided in Appendix B.

In the human NMP model, the parameter for rate of daily NMP ingestion in drinking water (DRINK, 

mg/kg/day) is included in the equation for rate of NMP change in the liver (RALiv), but should more 

appropriately be placed in the equation for rate of NMP change in the stomach (RSTOM). As a practical 

matter, the differences in NMP dose metrics from average daily drinking water doses being introduced in 

the liver compartment versus the stomach are likely to be negligible. 

3 NMP MODEL OUTPUT

Select simulations in rats and humans were run using the code with modification as outlined in Section 2 

(referred to hereafter as the modified EPA model). The resulting output was compared with output from 

the same simulations presented in the Poet (2013) report, which presented a metabolism re-optimized 

version of the model code relied upon in Poet et al. (2010), as well as experimental observations, where 

available. Figure 1 shows the comparative simulations of the Poet (2013) model, the modified EPA 
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model to the concentrations of NMP measured in blood following a single IV injection of 0.1 (Payan et 

al. 2002) or 45 mg/kg (Wells and Digenis 1988). Figure 2 provides model estimates of 5-HNMP 

concentrations in blood and urine, as well as the corresponding measured concentrations, following single 

IV injections of 0.1 – 500 mg/kg NMP (Payan et al. 2002). In both Figures, minimal differences were 

seen between the Poet (2013) and modified EPA models in predicting blood or urine levels of NMP and 

5-HNMP. 

Figure 3 shows measured and model estimated concentrations from both the Poet (2013) and modified 

EPA models of plasma NMP in rats following a single dermal application of 200 μL neat NMP (Payan et 

al. 2003). The Poet (2013) and modified EPA models replicated the experimental observations equally 

well, with slight over- and under-predictions of the plasma profiles, respectively. Thus, the modified EPA 

NMP model code is capable of reproducing plasma and urine profiles of NMP and 5-HNMP in rats.

The Poet (2013) and modified EPA models for NMP in humans were used to simulate acute inhalation 

and dermal exposures. Figures 4 and 5 provide the measured and model estimated concentrations (for 

both the Poet and modified EPA models) of NMP or 5-HNMP in blood or urine of volunteers inhaling 10 

-80 mg NMP/m3for six hours (Poet et al. 2010). Model-predicted NMP levels in plasma and 5-HNMP 

levels in plasma and urine using the modified EPA code were slightly closer to experimental observations 

at 39 and 80 mg/m3than were predictions using the Poet (2013) code. However, the Poet (2013) code 

predicted NMP in urine levels that were closer to experimental observations than predicted by the 

modified EPA model. The output from both model codes (Figure 6) produce very similar simulations of 

plasma NMP in human volunteers inhaling 10 – 53 mg/m3 NMP (Akesson and Paulsson 1997). 

For human dermal exposure simulations (Figures 7 and 8), the estimated plasma 5-HNMP concentrations 

from the modified EPA model code replicated the profiles of the experimental observations (Akesson et 

al. 2004), which was not the case for urinary 5-HNMP, in which model predictions using the modified 

EPA model for both males and females were approximately 25-30% lower than experimental 

observations (Figure 7). The lower model predictability of the urinary data may be due to lower urine 

production in the volunteers, compared to the assumed 2 L/day production used in the model. Lower urine 

volume in the experimental subjects could result in higher 5-HNMP levels, compared to model 

predictions. Finally, the dermal simulations of the Akesson et al. (2004) experiments using modified 

EPA code (Figure 9) comport with statements by Akesson et al. (2004) that 6-hour dermal exposures to 

neat NMP would likely result in similar plasma NMP levels to those seen previously following 10 mg/m3

inhalation exposures (Akesson and Paulsson 1997).

4 CONCLUSIONS

The NMP PBPK model code of Poet et al. (2010), as re-optimized by Poet (2013), for rats and humans, 

was modified by EPA and provided to ENVIRON for use in a QA assessment of the model for use in risk 

assessment. The modified EPA model code and the Poet (2013) models generally produced very similar 

simulations following IV and dermal exposures in rats and inhalation and dermal exposures in humans. 

The modified EPA model provides predictions of plasma NMP levels in both species that were closer to 

experimental observations than were urinary metabolite predictions. Thus, the modified EPA model code 

is capable of predicting parent compound and metabolite profiles from multiple data sets providing blood 

and urine measurements in rodents and humans exposed to NMP by multiple routes of exposure (IV, 

dermal and inhalation). 
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5 REFERENCES

Akesson, B., Carnerup, M. A. and Jonsson, B. A. (2004). Evaluation of exposure biomarkers from 

percutaneous absorption of N-methyl-2-pyrrolidone. Scand.J.Work Environ.Health 30, 306-312.

Akesson, B. and Paulsson, K. (1997). Experimental exposure of male volunteers to N-methyl-2-

pyrrolidone (NMP): acute effects and pharmacokinetics of NMP in plasma and urine. 

Occup.Environ.Med. 54, 236-240.

Brown, R. P., Delp, M. D., Lindstedt, S. L., Rhomberg, L. R., Beliles, R. P. (1997). Physiological 

parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13, 407-484.

Gentry, P. R., Covington, T. R., Andersen, M. E., and Clewell, H. J. III. (2002). Application of 

physiologically based pharmacokinetic model for Isopropanol in the derivation of a reference dose and 

reference concentration. Reg Toxicol Pharm 36, 51-68. 

Payan, J. P., Beydon, D., Fabry, J. P., Boudry, I., Cossec, B., and Ferrari, E. (2002). Toxicokinetics and 

metabolism of N-[14C]methylpyrrolidone in male Sprague-Dawley rats. A saturable NMP elimination 

process. Drug Metab. Dispos. 30, 1418–1424.

Payan, J. P., Boudry, I., Beydon, D., Fabry, J. P., Grandclaude, M. C., Ferrari, E. and Andre, J. C. (2003). 

Toxicokinetics and metabolism of N-[(14)C]N-methyl-2-pyrrolidone in male Sprague-Dawley rats: in 

vivo and in vitro percutaneous absorption. Drug Metab Dispos. 31, 659-669.

Poet, T. S., Kirman, C. R., Bader, M., van Thriel, C., Gargas, M. L. and Hinderliter, P. M. (2010). 

Quantitative Risk Analysis for N-Methyl Pyrrolidone Using Physiologically Based Pharmacokinetic and 

Benchmark Dose Modeling. Toxicol Sci 113, 468-482.

Poet.	(2013).		Internal Dose, as Derived from Updated PBPK Model, Should Be Basis for NMP Toxicity 

Assessment. Battelle Memorial Institute Pacific Northwest Division.

Wells, D. A., and Digenis, G. A. (1988). Disposition and metabolism of double-labeled [3h and 14c] Nmethyl-2-pyrrolidinone in the rat. Drug Metab. Dispos. 16, 243–249.
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

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Table 1. Differences between NMP PBPK model parameter values found in the provided 

model computer code and Poet et al. (2010) 

Species Parameter Parameter 

name

Value provided in 

model computer code

Value published by 

Poet et al. (2010)

Rat Molecular weight for 

5-HNMP MWHP 116.14 115.13

Rat Percent cardiac output to 

skin QSKNC 5.8 1.0

Rat Percent cardiac output to 

mammary gland QMAMC 0.1 0.2

Rat Percent cardiac output to 

uterus QUTRC 0.1 0.5

Rat

First-order urinary 

elimination rate of NMP 

(L/hr)

KLC 3.9 4.9

Rat Slowly-perfused tissue:blood 

NMP partition coefficient PS 0.74 0.57

Rat Lung tissue:blood NMP 

partition coefficient PLU 0.10 0.13

Human Molecular weight for 

5-HNMP (g/mol) MWHP 116.14 115.13

Human Percent cardiac output to 

skin QSKNC 5.8 3.0

Human Percent cardiac output to 

uterus QUTRC 0.5 0.62

Human NMP vapor permeability 

coefficient (cm/hr) PV 32 23
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Figure 1. Reproduction of Wells and Digenis (1988) and Payan et al. (2002) IV NMP 

exposures: Plasma profiles
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Figure 2. Reproduction of Payan et al. (2002) IV NMP exposures
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Figure 3. Reproduction of Payan et al. (2003) dermal NMP exposure
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Figure 4. Reproduction of Poet et al. (2010) inhalation NMP exposures: Blood profiles
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Figure 5. Reproduction of Poet et al. (2010) inhalation NMP exposures: Urine profiles
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Figure 6. Reproduction of Akesson and Paulsson (1997) inhalation NMP exposures
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Figure 7. Reproduction of Akesson et al. (2004) dermal NMP exposures
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Figure 8. Comparison of Akesson and Paulsson (1997) dermal with inhalation NMP 

exposures
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APPENDIX A. Modified AcslXtreme CSL and M Files Used for the QA Assessment

NMPPREG_RAT.CSL

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 IPA MODEL 

OF 

! GENTRY ET AL. REGU TOX PHARM 36:51-68, 2002

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. NOT USED IN HUMAN MODEL

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

CONSTANT MWHP= 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)
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 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

! NOTE 0.1 IS THE VALUE SUPPLIED BY ENVIRON AND USED FOR IPA, IT IS UNSURE WHERE THE VALUE 

COMES FROM

! GRAPHING OUT TRANSPORT TO FETUS, 0.1 RESULTS IN A MAX FOR NMP, MAYBE FOR IPA AS WELL

! TISSUE 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 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.*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 + 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) ! CHANGED 0.74 TO 0.75; PMS 8-19-13

 QFATI = QFATC * QCINIT

 QLIV = QLIVC * QCINIT

 QMAMI = QMAMC * QCINIT

 QRAP = QRAPC * QCINIT

 QSKN = QSKCC * QCINIT
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 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 (NOT USED FOR HUMAN, ASSUME 1)

 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

!EXPERIMENTALLY MEASURED VALUES

 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

! CODE FOR SKIN-AIR TRANSFER IS COMMENTED OUT BELOW, HENCE PSKA IS NOT USED; PAUL 

SCHLOSSER, U.S. EPA 5-17-13

! CONSTANT PSKL=0 !MEASURED

 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
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 CONSTANT PPLHNP=0

 

!METABOLIC RATE CONSTANTS

!**THESE ARE FROM PAYAN ET AL

 !NMP TO 5HNP

 CONSTANT KM=0 !MICHAELIS CONSTANT, MG/L

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

 VMAX1 = VMAXC*BWINIT**0.75

 

 !5HNP TO OTHER 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

!NOTE FIRST ORDER RATE COMMENTED OUT, SATURABLE FITS BETTER

 CONSTANT KLC=0

 KL=KLC/(BWINIT**0.25)

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

KLN=KLNC/(BWINIT**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 THIS MAY NEED SET LOWER FOR 

NEW VERSION OF ACSL TO RUN

 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 CHEMICAL (MG)

 CONSTANT CONCPPM = 0.0 !AIR CONCENTRATION IN PPM!
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CONSTANT CONCMGS = 0.0

! USED TO SET AIR CONC'N AS MG/M3, PMS, 8-13-13

 VCH = VCHC-(RATS*BWINIT) !VOLUME OF OCCUPIED CHAMBER

 CONCMG = CONCMGS/1000 + 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 * VCH !INIT. AMT IN CHAMBER, MG! 

 !ORAL

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

 CONSTANT DOSE=0.0 !ORAL DOSE IN MG/KG BW

 ODOSE = DOSE*BWINIT !CONVERT MG/KG BW TO MG TOTAL(ORAL)

 !**NOTE - CONSIDER ADDING ZERO ORDER FOR HUMAN HED

CONSTANT DOSE2=0.0 ! ORAL DOSE IN MG/KG

BW, BUT TOTAL DOSE INCREASES W/ BW

 !FEED

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

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

 ! TABLE FEEDDOSE 1 ,10 /10*24.,10*1./

 !IV 

 CONSTANT IVDOSE=0.0 !IV DOSE, MG/KG NMP

 CONSTANT TINF=0.01 !DURATION OF IV INFUSION, HR, SET TCHNG=TINF

 !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; 

PMS 8-14-13

ASKO=DSK*BWINIT ! PMS, 8-14-13

CONSTANT TWASH=8.0 ! WASH TIME IN BECCI ET AL. (1982) EXPOSURES

 !CONSTANT RESID=0 !AMOUNT STICKING TO EXPOSURE SYSTEM, MG

 ! DDN = CONCL*VLIQ

CONSTANT FAD=0.222 !FRAC NO ABSORBED IN PAYAN 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
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 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.TSTART

 ALGORITHM IALG=2 !GEAR ALGORITHM 

 

END

DYNAMIC

 

DERIVATIVE

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

 GDMONTH=GDMONTHS/0.64!TO WAG HUMAN GROWTH, THIS SETS HUMAN FETAL

!AT BIRTH ~3.5 KG AND MOTHER GAINING ~ 8.7 

KG

!ACTUAL HUMAN AT BIRTH AVERAGE IS 3.5 KG

!MOTHER AT BIRTH GAINS 13.6 KG

 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)

! ADDED 1.0E-8 TO VARIOUS VOLUMES TO AVOID DIVIDE-BY-ZERO PROBLEMS; PMS 8-13-13

 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))

! 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 
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 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)

 ! WATER=(0.0033*DAYS)+(9.2E-5*(DAYS**2)) !CORLEY ET AL CRC 03, 

 BW = BWINIT + (VFAT - VFATI) + VFET + (VMAM - VMAMI) + VPLA + (VUTR -

VUTRI)+(VLIV - VLIVI)

 

! SCALED ALVEOLAR VENTILATION (L/HR)

 QP = QPC * ((BW-VFET-VPLA)**0.75) ! CHANGED 0.74 TO 0.75; PMS 8-19-13

 

! INCREASE IN BLOOD FLOWS (L/HR)

 QFAT = QFATI * (VFAT / VFATI)

 QMAM = QMAMI * (VMAM / VMAMI)

 QUTR = QUTRI * (VUTR / VUTRI)

!!!!!! NOTE THAT THE BLOOD FLOWS NO LONGER BALANCE. QP HAS INCREASED BY THE ADDITIONAL 

!!!!!! FETAL AND PLACENTAL VOLUMES BUT THE COMPARTMENTAL FLOWS HAVE NOT CHANGED. 

!!!!!! QRECOV WILL START AT 100 AND DECREASE THRU PREGNANCY (PMH 25-APR-2007)

! TOTAL BODY FOR HNMP

 QB = QRAP+QSLW+QSKN+QMAM+QUTR ! +QPLA ! PLACENTA IS A SEPARATE COMPARTMENT; 

PMS 8-19-13

 VB = VRAP+VSLW+VLU+VSK+VMAM+VUTR ! +VPLA ! DITTO; PMS 8-19-13

! 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

 ELSE IF (DAYS.LE.12.0) THEN

 QPLA = (NUMFET * (2.2 * EXP(-0.23 * (DAYS - 10)))) / 24

 ELSE 
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 QPLA = (NUMFET * ((2.2 * EXP(-0.23 * (DAYS - 10)))+ ((0.1207 * (DAYS - 12.0))**4.36))) / 24

 ENDIF

! INCREASED CARDIAC OUTPUT (L/HR)

 !QC = QCINIT + (QFAT - QFATI) + (QMAM - QMAMI) + QPLA+ (QUTR - QUTRI)

 QC = QFAT+QLIV+QSLW+QRAP+QSKN+QMAM+QPLA+QUTR! PMS, 8-13-13

! SCALED PERMEABILITY-AREA PRODUCT

 PAF = PAFC * (VFET**0.75)

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

!EQUATIONS FOR ORAL GAVAGE DOSING 

 RAO = KAS * AO*FRACOR

 AO = INTEG(-RAO,ODOSE) !AMT REMAINING TO BE ABS, MG!

 OABS = INTEG(RAO,0.0) 

!ODOSE - AO !AMT ABSORBED ORALLY, MG!

!EQUATIONS FOR FEED DOSING 

 FDOSE = DOSEF*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

 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/TINF !RATE OF INFUSION, MG/HR

 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
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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/MWNMP

 CLOSS = INTEG(KLOSS * ACH,0.0)

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

PMS, 8-13-13

! LUNGS

 !RALU = (QP * ((FRACIN * CI) - CLEX)) + (QC * (CV - CVLU))

 RALU = (QP * ((FRACIN * CI) - CLEX)) + RVV - (QC * CVLU) ! PMS, 8-13-13

 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

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

 RASK = QSKN*(CA - CSKV) + RADL ! NOW MINUS CSKV, NOT CSK; PMS 8-21-13

 ASK = INTEG(RASK,ASKO) ! INITIAL VALUE, ASKO, ADDED FOR BECCI ET AL. (1982) EXPOSURES; 

PMS 8-14-13

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

CSKV = CSK/PSKB ! NMP IN VENOUS 

BLOOD, PMS 8-22-13

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

 ! RADL = (KPL*SA/1000)*(CONC2 - (CSK/PSKA))*DZONE !REPLACE CONCL W CONC2 IF LIQUID 

ABSORPTION NEEDED

 ! ADL = INTEG(RADL,0.0) !'AMT NMP ABSORBED DERMAL,MG'

 ! DDA=DDN-RESID !'LESS AMT NMP RECOVERED ON PATCH
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Page 25

 ! ADLA = INTEG(-RADL,DDA)

 ! ADL2 = ADL*1000/MWNMP !'AMT ABSORBED, MICROMOLES'

! CONC2=RSW(VLIQABS1.LE.VLIQ,ADLA/(VLIQ-VLIQABS1),0.01)

 ! VLIQABS1=ADL/1000/DENSITY/1000

CONCL2=CONCL*FAD

CSURF=(CONCL2-(ADL/VLIQ))*DZONE

!RADL=((KPL*SA/1000)*CSURF)-(CSK/PSK) ! INCORRECT FORM; PMS 8-13-13

RADL=(KPL*SA/1000.0)*((CSURF-(CSK/PSKL))*DZONE - (1.0-DZONE)*(CSK/PSKA)) ! CORRECT FORM; 

PMS 8-13-13

! 2ND TERM, (1.0-DZONE)*(CSK/PSKA), ALLOWS FOR EVAPORATIVE LOSS WHEN DZONE=0; PMS 8-14-13

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)

 !IF (DAYS.GT.6.0) CFET = AFET / VFET

CFET = AFET / VFET ! PMS, 8-13-13

 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)

 ! IF (DAYS.GT.6.0) CPLA = APLA / VPLA

CPLA = APLA / VPLA ! PMS, 8-13-13
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Page 26

 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

!RV=(QFAT*CVFAT+QLIV*CVL+QSLW*CVS+QRAP*CVR+QSKN*CSK+CVMAM*QMAM+CVPLA*QP

LA+QUTR*CVUTR+IVR)-QC*CV

RVV = QC*CV ! PMS, 8-13-13

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

LA+QUTR*CVUTR+IVR)-RVV ! PMS, 8-13-13

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+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)
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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

! ** ADDED QPLA*CVPLHP TO ABOVE; PMS 8-19-13

 AVHP = INTEG (CRHP,0.0)

 CVHP = AVHP/VBL

 CAHP = CVHP

 CVHP2 = CVHP*1000/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)

 !IF (DAYS.GT.6.0) CPLHP = APLHP / VPLA

CPLHP = APLHP / VPLA ! PMS, 8-13-13

 CVPLHP = CPLHP / PPLHNP

 

 ! AMOUNT IN FETUSES (MG)

 RAFETHP = PAF * (CPLHP - CFETHP)

 AFETHP = INTEG(RAFETHP, 0.0)

 ! IF (DAYS.GT.6.0) CFETHP = AFETHP / VFET

CFETHP = AFETHP / VFET ! PMS, 8-13-13

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

!COMMENT OUT EQUATIONS WHEN NOT USING TO ELIM. UNESSESARY INTEG

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

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

! CHECK BLOOD FLOWS 5HNMP COMPARTMENT

 QTOTH = QLIV + QFAT + QB+QPLA
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

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 QRECOVH = 100.0 * (QTOTH / QC)

TERMT(T .GE. TSTOP) !----STATEMENT TO STOP EXECUTION---

END !END OF DERIVATIVE

DISCRETE GAVD

AO = AO + DOSE2*BW

SCHEDULE GAVD .AT. (T+24.0)

END

!EXPOSURE CONTROL

DISCRETE SKWASH ! PMS, 8-14-13

ASK = 0.0 ! ASSUME SKIN WASHING IN BECCI ET AL. (1982) REMOVES ALL NMP FROM SKIN

IF (DAYS.LT.15.0) SCHEDULE REAPPLY.AT.(T+DOSEINTERVAL-TWASH)

END

DISCRETE REAPPLY ! PMS, 8-14-13

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

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) ! PMS, 8-13-13

END

DISCRETE OND ! PMS, 8-13-13

 CIZONE=1.0 !TURN INHAL EXPOSURE ON

SCHEDULE OFFD.AT.(T+TCHNG)

END

END !END OF DYNAMIC

END !END OF PROGRAM
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HUMPREGRETRIEVE_RESTORED_1.CSL

PROGRAM NMPHUMPG.ACSL

!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)

INITIAL

TABLE RESLVL, 1, 1441 / 1441*0.0, 1441*0.0 /

! HUMAN TOTAL PULMONARY VENTILATION RATE (L/HR FOR 1 KG ANIMAL)
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 30

 CONSTANT QPC = 27.75

! HUMAN BLOOD FLOWS (FRACTION OF CARDIAC OUTPUT)

 CONSTANT QCC = 12.9 ! CARDIAC OUTPUT (L/HR FOR 1 KG ANIMAL)

 CONSTANT QFATC = 0.052 ! FAT (NON-PREGNANT FEMALE)

 CONSTANT QLIVC = 0.227 ! LIVER

 CONSTANT QMAMC = 0.027 ! MAMMARY TISSUE (NON-PREGNANT FEMALE)

 CONSTANT QRAPC = 0.325 ! RAPIDLY PERFUSED

 CONSTANT QSKC = 0.058 ! SKIN

 CONSTANT QUTRC = 0.0062 ! UTERUS (NON-PREGNANT FEMALE)

! GENTRY MODEL HAS 0.249, BUT ADDING THESE =0.944, SO BE AWARE CAN REPLACE WITH EQN

! PERMEABILITY-AREA PRODUCT (L/HR)

 CONSTANT PAFC = 0.01 ! DIFFUSION ON FETAL SIDE OF PLACENTA

 ! NOT SURE WHERE OPTIMIZED PARAMETER COMES FROM VISAVIS 

GENTRY

! HUMAN TISSUE VOLUMES (FRACTION OF BODY WEIGHT)

 CONSTANT BWINIT = 67.8 ! PRE-PREGNANCY BODY WEIGHT (KG)

 CONSTANT VALVC = 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 VSLWC = 0.35 ! SLOWLY PERFUSED IN GENTRY MODEL, THIS MODEL IS CALCULATED 

BELOW

 CONSTANT VUTRC = 0.0014 ! UTERUS (NON-PREGNANT FEMALE)

 CONSTANT VSKC=0.19

! HUMAN DERMAL EXPOSURE PARAMETERS

 CONSTANT P = 0.0016 ! PERMEABILITY CONSTANT (KP) (CM/HR)

 CONSTANT PV=31.0 ! PERMEABILITYT CONSTANT (CM/HR) 

FOR VAPOR

 

 

!FOR PARENT MODEL, SKIN COMPARTMENT IS ONLY DEFINED AS DOSED SKIN

 CONSTANT SAL = 0.01 !SURFACE AREA EXPOSED TO LIQUID, SQ.CM

 CONSTANT SAV = 6700 !SURFACE AREA EXPOSED TO GAS/VAPOR, SQ.CM

 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

 VSKLC = VSKC*SAL/TSA

 QSKLC = QSKC*SAL/TSA

 VSKVC = VSKC*SAV/TSA

 QSKVC = QSKC*SAV/TSA

! CONSTANT DERM=0 !DERMAL DOSE - MG (AMOUNT)

! DERM NOT USED IN REST OF CODE; PAUL SCHLOSSER, U.S. EPA (PS), 5-17-2013
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Page 31

CONSTANT FAD = 0.0 !FRACTION ABSORBED - FROM BADER ET AL, CALCULATE FROM AMNT 

REMAINING ON GAUZE

CONSTANT PVL=0.0

 

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

 VSLWC = 0.91 - ( VFATC + VLIVC + VMAMC + VRAPC + VUTRC + VSKVC + VSKLC) !VLUC + ! PMS 8-20-13, 

REMOVED + VALVC

 ! NOTE: 0.91 IS APPROX WHOLE BODY LESS BONE

 VSLWC5=0.91 - (VFATC + VLIVC + VRAPC) ! PMS 8-20-13, REMOVED + VALVC 

 QSLWC = 1.0 - (QFATC + QLIVC + QMAMC + QRAPC + QUTRC + QSKVC + QSKLC)

 QSLWC5 = 1.0 - (QFATC + QLIVC + QRAPC)! + QSKCC)

 

! MOLECULAR WEIGHTS

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

CONSTANT MW1= 116.14 !MOL. WT. 5-HNP, MG/MMOL

 STOCH = MW1/MW

! HUMAN NMP/BLOOD PARTITION COEFFICIENTS

!EXPERIMENTALLY MEASURED RATVALUES

 CONSTANT PB = 450.0 ! BLOOD/AIR

 CONSTANT PFAT = 0.61 ! FAT

 CONSTANT PLIV = 1.00 ! LIVER

 CONSTANT PMAM = 1.0 ! MAMMARY TISSUE, ESTIMATED FROM LIVER

 CONSTANT PPLA = 0.31 ! PLACENTA

 CONSTANT PRAP = 1.0 ! RAPIDLY PERFUSED TISSUE, LIVER

 CONSTANT PSLW = 0.30 ! SLOWLY PERFUSED TISSUE, MUSCLE

 CONSTANT PUTR = 0.34 ! UTERUS

 CONSTANT PSKA = 44.5 !450.0 ! USE (BLOOD/AIR)*(RAT SKIN:LIQUID)/(HUMAN 

BLOOD:LIQUID)

 CONSTANT PSKL = 0.42 ! MEASURED SKIN;LIQUID (RAT)

CONSTANT PSKB = 0.099 ! (RAT SKIN:LIQUID)/(HUMAN BLOOD:LIQUID)

 CONSTANT PLU= 0.1 ! LUNG:BLOOD

 

!METABOLIC RATE CONSTANTS

!**THESE ARE FROM PAYAN ET AL

 !NMP TO 5HNP

 CONSTANT KM=198.0 !MICHAELIS CONSTANT, MG/L

 CONSTANT VMAXC=2.67 !MAX. ENZ. ACT., MG/HR/L

! HUMAN 5HNMP TISSUE/BLOOD PARTITION COEFFICIENTS

! MEASURED

 CONSTANT PB1=5.0

 CONSTANT PLIV1=3.0 ! LIVER MEASURED

 CONSTANT PFAT1=0.40 !MEASURED

 CONSTANT PRAP1=0.93

 CONSTANT PSLW1=0.40

 !NO FETAL COMPARTMENT FOR METABOLITE, NMP IS CONSIDERED THE ACTIVE MOIETY 
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Page 32

!5HNP TO OTHER METABS

 CONSTANT KM2=22.8 !MICHAELIS CONSTANT, MG/L

 CONSTANT VMAX2C=1.0 !MAX. ENZ. ACT., MG/HR/L

 

! 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=8.0 !MICHAELIS CONSTANT, MG/L

 CONSTANT VMAXEC=8.0 !MAX. ENZ. ACT., MG/HR/L

 CONSTANT KMNE=8.0 !MICHAELIS CONSTANT FOR NMP IN URINE

 CONSTANT VMXNEC=1.0

 

! INITIALIZE HUMAN CONCENTRATIONS IN TISSUES (MG/L)

 CONSTANT ICART = 0.0 ! BLOOD

 CONSTANT ICFAT = 0.0 ! FAT

 CONSTANT ICLIV = 0.0 ! LIVER

 CONSTANT ICRAP = 0.0 ! RAPIDLY PERFUSED

 CONSTANT ICSKN = 0.0 ! SKIN

 CONSTANT ICSLW = 0.0 ! SLOWLY PERFUSED

 ICMAM = ICSLW ! MAMMARY TISSUE

 ICUTR = ICRAP ! UTERUS

! DOSING PARAMETERS

 CONSTANT CONCPPM = 0.0 ! INHALED CONCENTRATION (PPM)

 CONSTANT CONCMGM = 0.0 ! INHALED CONCENTRATION (MG/M3)

 CONSTANT IVDOSE = 0.0 ! IV DOSE (MG/KG)

 CONSTANT PDOSE = 0.0 ! ORAL DOSE (MG/KG)

CONSTANT PDOSE2=0.0

CONSTANT PDOSE3=0.0

 CONSTANT PDRINK = 0.0 ! DRINKING WATER DOSE (MG/KG/DAY)

 CONSTANT TCHNG = 24.0 ! LENGTH INH. EXPOSURE OR IV INJ.(HRS)

 CONSTANT DAYSWK = 5.0 ! NUMBER OF EXPOSURE DAYS PER WEEK

 CONSTANT TMAX = 24.0 ! MAXIMUM TIME FOR EXPOSURES

CONSTANT S2=0.0

!INHALATION ON

CONSTANT P2=3.0

!INHALATION EXPOSURE

CONSTANT S3=3.16 !INHALTION 

RESUME (HANOVER STUDY)

CONSTANT P3=3.0

!SECOND DAILY EXPOSURE PERIOD

CONSTANT ON3=1.0 ! SET TO ZERO TO TURN OFF 2ND DAILY PULSE; PMS 8-20-13

CONSTANT FULLWEEK=168.0 ! HRS IN A FULLWEEK; PMS 8-20-13

HRSWEEK=24.0*DAYSWK ! HRS/WEEK IN WORKPLACE; PMS 8-20-13

! STARTDS IS ADDED TO TCHNG TO ALLOW FOR DOSING THAT DOES NOT START AT T=0

!INITIAL EXPOSURE CONDITIONS

!DERMAL
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 33

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

CONSTANT SRATE = 0.0 ! MG/HR DELIVERED TO SKIN BY SPRAY 

APPLICATION; PMS 8-20-13

 CONSTANT VLIQ = 1.0E-99 !INITIAL VOLUME APPLIED, L

 CONSTANT DENSITY=1.03

 CONSTANT RESID=0.0 !AMOUNT STICKING TO EXPOSURE SYSTEM, MG

CONSTANT BRUSH=0.0 ! SET TO 1.0 FOR BRUSH/LIQUID 

EXPOSURE; PMS 8-20-13

 DDN = CONCL*VLIQ

 !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 !CONCERT MG/M3 TO 

MG/L

 ELSE

 CONCMG = CONCPPM*MW/24451. !CONVERT PPM TO MG/LITER!

 ENDIF

!CONSTANT CONCMG=0

!HANNOVER STUDY UNIT MG/M3 SO CONCMG /1000(L/M3) 

CONSTANT DOSEINTERVAL=24.0 !TIME BETWEEN DAILY DOSES

 

! SIMULATION CONTROL PARAMETERS

 CONSTANT STARTDS = 0.0 ! TIME FIRST DOSE IS GIVEN (HRS)

 CONSTANT TSTOP = 6480.0 ! RUN SIMULATION FOR ABOUT 9 MONTHS

 CONSTANT CINTC = 0.1

CONSTANT GDSTART = 0.0 ! GESTATION DAY ON WHICH SIMULATION STARTS; PMS 

8-20-13

! SCALED HUMAN PULMONARY VENTILATION RATE (L/HR)

 QP = QPC * (BWINIT**0.75)

 QALV = 0.67 * QP

! SCALED HUMAN BLOOD FLOWS (L/HR)

 QCINIT = QCC * (BWINIT**0.75)

 QFATI = QFATC * QCINIT

 QLIV = QLIVC * QCINIT

 QMAMI = QMAMC * QCINIT

QPLAI = 58.5 * VPLAI ! VALUE FOR 'DAYS'=0 PER CALCULATION BELOW; PMS, 8-20-13

 QRAP = QRAPC * QCINIT

 QSLW = (QSLWC * QCINIT) - QPLAI ! - QSKCC ! QSKCC IS ALREADY SUBTRACTED IN SETTING QSLWC 

ABOVE; PMS 8-20-13

! BUT INITIAL PLACENTAL BLOOD FLOW IS NOT, SO NOW SUBTRACTED 

HERE; PMS 8-20-13

 ! QSLW5= (QSLWC5* QCINIT) ! WILL CALCULATE BY SUBTRACTION IN THE DERIVATIVE SECTION; PMS 

8-1913
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 34

 QUTRI = QUTRC * QCINIT

 QSKL = QSKLC * QCINIT

 QSKV = QSKVC * QCINIT

! SCALED HUMAN TISSUE VOLUMES (L)

 VALV = VALVC * BWINIT

 !VFATI = VFATC * BWINIT

 VFATI = BWINIT*(VFATC+(0.09*EXP(-12.90995862*EXP(-0.000797*24.0*GDSTART))))

 VFETI = 3.50 * (EXP(-16.081*EXP(-5.67E-4*24.0*GDSTART))+ EXP(-140.178*EXP(-7.01E4*24.0*GDSTART)))

 !VMAMI = VMAMC * BWINIT

 VMAMI = BWINIT*(VMAMC+(0.0065*EXP(-7.444868477*EXP(-0.000678*24.0*GDSTART))))

!VPLAI = 0.85*EXP(-9.434) ! VALUE FOR 'DAYS'=0 PER CALCULATION BELOW; PMS 

8-19-13

 VPLAI = 0.85*EXP(-9.434*EXP(-5.23E-4*24.0*GDSTART))

 !VUTRI = VUTRC * BWINIT

 VUTRI = BWINIT*(VUTRC+(0.02*EXP(-4.715669973*EXP(-0.000376*24.0*GDSTART))))

 VLIV = VLIVC * BWINIT

 VRAP = VRAPC * BWINIT

 VSKL = VSKLC * BWINIT

 VSKV = VSKVC * BWINIT

 VBL=VBLC * BWINIT

 VSLW = (VSLWC * BWINIT) ! - VSKCC; PMS 8-20-13

 ! VSLW5 = VSLWC5 *BWINIT ! NOW CALCULATED BY SUBTRACTION IN DERIVATIVE SECTION; PMS 8-

20-13

! SCALED HUMAN METABOLISM PARAMETERS

 VMAXE = VMAXEC*(BWINIT**0.75) !URINE 5HNMP

 VMXNE=VMXNEC*(BWINIT**0.75) !URINE NMP

 VMAX = VMAXC * (BWINIT**0.75)

 VMAX1 = VMAX2C * (BWINIT**0.75)

 

! INITIALIZE HUMAN NMP AMOUNTS IN TISSUES

 IAART = ICART * VALV

 IAFAT = ICFAT * VFATI

 IALIV = ICLIV * VLIV

 IAMAM = ICMAM * VMAMI

 IARAP = ICRAP * VRAP

 IASKL = ICSKN * VSKL ! VSKCC ! PMS 8-20-13

 IASKV = ICSKN * VSKV

 IASLW = ICSLW * VSLW

 IAUTR = ICUTR * VUTRI

 INITTOT = IAART + IAFAT + IALIV + IAMAM + IARAP + IASKL + IASKV + IASLW + IAUTR

! INITIALIZE STARTING VALUES

 BW = BWINIT

 DRINK = (PDRINK * BW) / 24.0 ! DRINKING WATER DOSE (MG/HR)
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Page 35

 CINT = CINTC

 IV = 0.0

 DAYEXP = 1.0

 CINH = 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 

ODOSE1= PDOSE * BW * FRACOR ! UMOLES

ODOSE2= PDOSE2* BW * FRACOR ! UMOLES

ODOSE3= PDOSE3* BW * FRACOR ! UMOLES

CONSTANT TIME=0.0

CONSTANT TIME1 = 0.0 ! !'DAILY RAT EXPO (HR)' 

CONSTANT TIME2 = 4.0 ! !'SECOND DAILY EXPOSURE (HR)' 

CONSTANT TIME3 = 4.0 ! !'THIRD DAILY DOSE'

CONSTANT REPTM=720.0 ! CHANGE TO 24 FOR DAILY DOSING

SCHEDULE DOSE1 .AT. TIME1

DZONE = 1.0 ! START WITH EXPOSURE ON

SCHEDULE OFFD.AT.P2

SCHEDULE OND2.AT.24.0

IF (ON3) SCHEDULE OND3.AT.S3

END ! END OF INITIAL

DYNAMIC

 ALGORITHM IALG = 2 ! GEAR STIFF METHOD

DISCRETE DOSE1

ODOSE = ODOSE+ODOSE1

SCHEDULE DOSE2 .AT. (TIME+TIME2)

END

DISCRETE DOSE2

ODOSE = ODOSE+ODOSE2

SCHEDULE DOSE3 .AT. (TIME+TIME3)

END

DISCRETE DOSE3

ODOSE = ODOSE+ODOSE3

SCHEDULE DOSE1 .AT. (TIME+REPTM-TIME2-TIME3)

END
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DISCRETE DOSEON ! START DOSING

 INTERVAL DOSEINT = 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(CINTC, (TCHNG/10.0))

 IV = (IVDOSE*BW) / TCHNG ! RATE OF INTRAVENOUS DOSING (MG/HR)

ENDIF

ENDIF

END ! DOSEON

DISCRETE DOSEOFF

 CINH = 0.0

 CINT = CINTC

 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

END

DERIVATIVE

 HOURS = T

 MINUTES = T * 60.0

 DAYS = T / 24.0 + GDSTART ! PMS 8-20-13, ADDED GDSTART

GTIME = T + GDSTART*24.0 ! PMS 8-20-13, REPLACES "T" IN TISSUE VOLUME CALCS 

BELOW

! 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))))
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Page 37

! VOLUME OF HUMAN PLACENTA (L)

 VPLA = 0.85*EXP(-9.434*EXP(-5.23E-4*GTIME))

! 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 - VFATI) + VFET + (VMAM - VMAMI) + VPLA + (VUTR - VUTRI)

! SCALED HUMAN ALVEOLAR VENTILATION (L/HR)

 QP = QPC * (BW**0.75)

 QALV = 0.67 * QP

! INCREASE IN HUMAN BLOOD FLOWS (L/HR)

 QFAT = QFATI * (VFAT / VFATI)

 QMAM = QMAMI * (VMAM / VMAMI)

 QUTR = QUTRI * (VUTR / VUTRI)

! HUMAN BLOOD FLOW TO PLACENTA (L/HR)

 QPLA = 58.5 * VPLA

! INCREASED HUMAN CARDIAC OUTPUT (L/HR)

 ! QC = QCINIT + (QFAT - QFATI) + (QMAM - QMAMI) + (QPLA) + (QUTR - QUTRI) 

 QC = QCINIT + (QFAT - QFATI) + (QMAM - QMAMI) + (QPLA - QPLAI) + (QUTR - QUTRI) 

! NOW SUBTRACTING QPLAI ABOVE; PMS 8-20-13

QSLW5 = QC - (QFAT + QLIV + QRAP) ! PMS, 8-20-13

VSLW5 = BW - (VFAT + VLIV + VRAP) ! PMS, 8-20-13

! SCALED PERMEABILITY-AREA PRODUCT

 PAF = PAFC * (VFET**0.75)

! ------------------ HUMAN NMP MODEL -------------------------

! AMOUNT EXHALED (MG)

 RAEXH = QALV * CALV

 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(0,1E6,24)

TORAL= ODOSE1 - AO !AMT ABSORBED ORALLY, MG!

RSTOM = -KAS*AO

RAO = KAS*AO ! CHANGE IN STOMACH (UMOLE/HR) 

AO=ODOSE1+INTEG(RSTOM,0.0) ! AMT IN STOMACH (UMOLE) 
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 38

! AMOUNT IN FAT (MG)

 RAFAT = QFAT * (CART - CVFAT)

 AFAT = INTEG(RAFAT, IAFAT)

 CFAT = AFAT / VFAT

 CVFAT = CFAT / PFAT

! AMOUNT IN FETUS (MG)

 RAFET = PAF * (CPLA - CFET)

 AFET = INTEG(RAFET, 0.0)

 CFET = AFET / VFET

 AUCCFET = INTEG(CFET, 0.0)

 

! AMOUNT IN LIVER (MG)

 RALIV = (QLIV * (CART - CVLIV)) + RAO + DRINK - RAMET1

 ALIV = INTEG(RALIV, IALIV)

 CLIV = ALIV / VLIV

 CVLIV = CLIV / PLIV

! AMOUNT METABOLISED IN LIVER -- SATURABLE (MG)

 RAMET1 = (VMAX * CVLIV) / (KM + CVLIV)

 AMET1 = INTEG(RAMET1, 0.0)

! AMOUNT IN MAMMARY TISSUE (MG)

 RAMAM = QMAM * (CART - CVMAM)

 AMAM = INTEG(RAMAM, IAMAM)

 CMAM = AMAM / VMAM

 CVMAM = CMAM / PMAM

 

! AMOUNT IN PLACENTA (MG)

 RAPLA = (QPLA * (CART - CVPLA)) + (PAF * (CFET - CPLA))

 APLA = INTEG(RAPLA, 0.0)

 CPLA = APLA / VPLA

 CVPLA = CPLA / PPLA

 

! AMOUNT IN RAPIDLY PERFUSED TISSUE (MG)

 RARAP = QRAP * (CART - CVRAP)

 ARAP = INTEG(RARAP, IARAP)

 CRAP = ARAP / VRAP

 CVRAP = CRAP / PRAP

!ASKL = AMOUNT NMP IN LIQUID-EXPOSED SKIN TISSUES (MG) AND DERMAL DOSING (FROM VAPOR)

! EQUATIONS BELOW SET FOR LIQUID-EXPOSED SKIN, PMS 8-21-13

 RASKL = QSKL*(CART - CVSKL) + RADVL+RASL

 ASKL = INTEG(RASKL,0.0)

 ! CVSKL = ASKL/VSKL !(VSKCC) ! PMS 8-20-13

 ! CSKL = CVSKL/PSKL !'NMP IN SKIN, MG/L'

 CSKL = ASKL/VSKL !(VSKCC) ! CALCULATION OF VENOUS BLOOD AND TISSUE CONCN'S WAS 

REVERSED; PMS 8-21-13

 CVSKL = CSKL/PSKB !'NMP IN SKIN, MG/L'
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 39

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

CZONE = PULSE(0.0,FULLWEEK,HRSWEEK)*DZONE ! PMS 8-20-13

! FOR A 5 DAY/WK EXPOSURE, USE FULLWEEK=7*24, HRSWEEK=5*24 (DAYSWK=5)

! FOR A SINGLE DAY, FULLWEEK=1E16, HRSWEEK=24 (DAYSWK=1)

SDELIV=SRATE*CZONE ! CONSTANT-RATE SPRAY DELIVERY; PMS 8-20-13

! SPRAY-DERMAL EXPOSURES, ASSUMED SIMULTANEOUS WITH INHALATION

 RADVL = (PV*SAL/1000.0)*(CI - (CSKL/PSKA))*(1.0-CZONE)*(SDELIV.EQ.0.0) + SDELIV

! RADV ALLOWS ABSORPTION/DESORPTION FROM AIR WHEN THERE IS 

NOT SPRAY OR

! BRUSHING DERMAL EXPOSURE, WHEN BOTH SDELIV AND DZONE ARE 

ZERO; PMS 8-20-13

 ADVL = INTEG(RADVL,0.0) !'AMT NMP ABSORBED DERMAL,MG'

CONCL2=CONCL*FAD

CSURF=CONCL2-(ADSL/VLIQ) ! FOR APPLICATIONS WIH NEAR-CONSTANT CSURF, SET VLIQ=1E9 OR 

HIGHER; PMS 8-2-13

RASL=(PVL*SAL/1000.0)*(CSURF-(CSKL/PSKL))*CZONE*BRUSH

!RASL=((PVL*SA/1000)*CSURF)-(CVSK/PSKL)

ADSL=INTEG(RASL,0.0)

 

!ASKV = AMOUNT NMP IN VAPOR-EXPOSED SKIN TISSUES (MG) AND DERMAL DOSING (FROM VAPOR); 

PMS 8-21-13

 RASKV = QSKV*(CART - CVSKV) + RADVV

 ASKV = INTEG(RASKV,0.0)

 ! CVSKV = ASKV/VSKV !(VSKCC) ! PMS 8-20-13

 ! CSKV = CVSKL/PSKV !'NMP IN SKIN, MG/L'

 CSKV = ASKV/VSKV !(VSKCC) ! PMS 8-20-13

 CVSKV = CSKV/PSKB !'NMP IN SKIN, MG/L'

!CONCDERM=CONCMG* PULSE(0,1E6,24)*(PULSE(S2,24,P2)+ PULSE(S3,24,P3))

! RADVV = (PV*SA/1000.0)*(CONCDERM - (CVSKV/PSKA))!*DZONE

 RADVV = (PV*SAV/1000.0)*(CI - (CSKV/PSKA))

 ADVV = INTEG(RADVV,0.0) !'AMT NMP ABSORBED DERMAL,MG'

! AMOUNT IN SLOWLY PERFUSED TISSUE (MG)

 RASLW = QSLW * (CART - CVSLW)

 ASLW = INTEG(RASLW, IASLW)

 CSLW = ASLW / VSLW

 CVSLW = CSLW / PSLW

! AMOUNT IN UTERUS (MG)

 RAUTR = QUTR * (CART - CVUTR)

 AUTR = INTEG(RAUTR, IAUTR)

 CUTR = AUTR / VUTR

 CVUTR = CUTR / PUTR

! BLOOD VENOUS ARTERIAL (C) 

CVEN=(QFAT*CVFAT + QLIV*CVLIV + QMAM*CVMAM + QPLA*CVPLA + QRAP*CVRAP + QSLW*CVSLW &

 + QUTR*CVUTR + QSKV*CVSKV + QSKL*CVSKL + IV) / QC
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 40

!(QFAT + QLIV + QMAM + QPLA + QRAP + QSLW+ QUTR + QSKV + QSKL) / QC

 ! TOTAL VENOUS BLOOD

!RABL= QC * (CVEN - CART) ! RATE OF CHANGE IN MIXED BLOOD 

!ABL= INTEG(RABL,0.0) ! AMOUNT IN MIXED BLOOD 

! ABOVE NOT USED; PMS 8-21-13

! AMOUNT IN ARTERIAL BLOOD (MG)

 RABLD = QALV*(CI*FRACIN - CALV) + QC*(CVEN-CART) - RAUNP

 ABLD = INTEG(RABLD, IAART)

 CART = ABLD / VBL

 CALV = CART / PB

 CALVPPM = CALV * 24450.0 / MW

 AUCCBLD = INTEG(CART, 0.0)

! AMOUNT IN URINE (MG)

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

 RAUNP = VMXNE*CART/(KMNE+CART) !SATURABLE ELIMINATION

AUNP = INTEG(RAUNP,0.0)

! -------------------- HUMAN 5HNMP MODEL --------------------------

! AMOUNT EXHALED (MG)

! RAEXH1 = QALV * CALV1

! AEXH1 = INTEG(RAEXH1, 0.0)

! CALVPPM1 = CALV1 * (24450.0 / MW1)

! AMOUNT IN FAT (MG)

 RAFAT1 = QFAT * (CART1 - CVFAT1)

 AFAT1 = INTEG(RAFAT1, 0.0)

 CFAT1 = AFAT1 / VFAT

 CVFAT1 = CFAT1 / PFAT1

! AMOUNT IN LIVER (MG)

 RALIV1 = ((QLIV * (CART1 - CVLIV1)) + (RAMET1*STOCH)) - RAMETM1

 ALIV1 = INTEG(RALIV1, 0.0)

 CLIV1 = ALIV1 / VLIV

 CVLIV1 = CLIV1 / PLIV1

! AMOUNT METABOLISED IN LIVER -- SATURABLE (MG)

 RAMETM1 = (VMAX1 * CVLIV1) / (KM2 + CVLIV1)

 AMETM1 = INTEG(RAMETM1, 0.0)

! AMOUNT IN RAPIDLY PERFUSED TISSUE (MG)

 RARAP1 = QRAP * (CART1 - CVRAP1)

 ARAP1 = INTEG(RARAP1, 0.0)

 CRAP1 = ARAP1 / VRAP

 CVRAP1 = CRAP1 / PRAP1

! AMOUNT IN SLOWLY PERFUSED TISSUE (MG)
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 41

 RASLW1 = (QSLW5) * (CART1 - CVSLW1)

 ASLW1 = INTEG(RASLW1,0.0)

 CSLW1 = ASLW1 / VSLW5

 CVSLW1 = CSLW1 / PSLW1

! CONCENTRATION IN MIXED VENOUS BLOOD (MG/L)

 CVEN1 = (QFAT*CVFAT1 + QLIV*CVLIV1 + QRAP*CVRAP1 +QSLW5*CVSLW1)/QC

 RART1 = QC*(CVEN1-CART1)-RAUHP

 ABLD1=INTEG(RART1,0.0)

 CART1 = ABLD1/VBL

! AMOUNT IN ARTERIAL BLOOD (MG)

 !CALV1 = CART1 / PB1

 AUCCBLD1 = INTEG(CART1, 0.0)

! AMOUNT IN URINE (MG)

 RAUHP = VMAXE*CART1/(KME+CART1) !SATURABLE ELIMINATION

!RAUHP=KLC*CART1

AUHP = INTEG(RAUHP,0.0)

INHALTOT=INTEG((QALV*(CI*FRACIN - CALV)), 0.0)

IVTOT=INTEG(IV, 0.0)

! ----------------- CHECK MASS BALANCE ------------------------------

 INTOT=INTEG((QALV*CI*FRACIN), 0.0)

! NEW SKIN TERMS ADDED BELOW; PMS 8-21-13

 TDOSE = INTOT + AO + INITTOT+TORAL+ADSL+ADVL+ADVV !+ INTEG(IV, 0.0)

 NMPTOT = ABLD + AFAT + AFET + ALIV + AMAM + APLA + ARAP + ASKL + ASKV + ASLW + AUTR + AEXH 

+ AUNP + AMET1

 MASSBAL = TDOSE/(NMPTOT+0.000000000001)

 

TERMT(T.GT.TSTOP, 'SIMULATION FINISHED')

END ! END OF DERIVATIVE

TERMINAL

 DAUCCBLD = (AUCCBLD / TSTOP) * 24.0

 DAUCCBLD1 = (AUCCBLD1 / TSTOP) * 24.0

 DAUCTOT = DAUCCBLD + DAUCCBLD1

 DAUCCFET = (AUCCFET / TSTOP) * 24.0

 DAUCTFET = DAUCCFET

END

END ! END OF DYNAMIC

END ! END OF PROGRAM
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 42

RATPARAMS.M

WESITG=0; WEDITG=0;

VCHC=1e9, KLOSS=0.0, DOSE=0,TINF=0.01,PDOSE=0,DOSE2=0, CONCCHPPM0 = 0

 CONCL=0, IVDOSE=0, TCHNG=999.0,TSTOP=120,CONCPPM=0,CONCMGS=0,DSK=0

%FAD=0.76 % Value from Payanderm.m; should only effect dermal exposure; PS 5-1-13

FAD=1 % From Poet 5-16-13 Payanderm.m file; PS 5-17-13

 GDDAYS=0, SA=0.00001,DOSEINTERVAL=720,CINT=1, VLIQ=1e-99, 

FRACIN=1 %1E-55 % Changed to 1 to match ghantinahladata.m value; should not change w/ exposure 

route; PS 5-1-13

NUMFET=0.01 % Added to minimize impact on other volumes; Paul Schlosser (PS), U.S. EPA, 05-01-2103

KAS=1.36,FRACOR=0.68

 % KPL=0.0000016

%KPL=4.3e-3 % Value from Payanderm.m; should only effect dermal exposure; PS 5-1-13

KPL=4.6e-3 % From Poet 5-16-13 Payanderm.m file; PS 5-17-13

 VLIVC=0.0366

 VLUC=0.005

 VFATC=0.09

 VRAPC=0.071

 QLIVC=0.183

 QPC=16.0

 QCC=16.0

 QFATC=0.07

 QSKNC=0.058

 QMAMC=1e-5

 QUTRC=1e-5

 KM=234

 VMAXC=21.8

 KM2=48

 VMAX2C=2.4

 QSC=0.14

 BWINIT=0.23

 GDDAYS=0

 GDMONTHS=0

 KLC=3.9

 KLNC=0.0019

 PAFC=0

 MAXT=1e-2

 MINT=1E-9

QFATC = 0.072 

QLIVC = 0.183

QMAMC = 0.001

QSKNC = 0.058

QUTRC = 0.001

QRAPC = 0.512

 

VLUC = 0.007
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 43

VFATC = 0.10

VLIVC = 0.034 

VMAMC = 0.01

VRAPC = 0.071 

VUTRC = 0.002 

VBLC = 0.067

 

PB=450.0

PF=0.62

PL=1.02

PR=1.02

PS=0.74

PLU=0.10

%PSKA= 450.0 %Air-skin transport equations, where PSKA appears, are commented

% out in Poet 5-15-13 NMPpreg_rat.m; PS 5-17-13

%PSK=150

PSKL = 0.42 % MEASURED % 450 % Value for Poet 5-16-13 Payanderm.m file; PS 5-17-13

PSKB = 0.12 % SKIN:SALINE/BLOOD:SALINE

PSKA = 55 % SKIN:SALINE*BLOOD:AIR/BLOOD:SALINE

PM=1.0

PPLA=0.309

PUTR=0.34

PLHNP=3.0

PBHNP=0.73

PFHNP=0.40

PPLHNP=01.07
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 44

PREG_RAT_PARAMS.M

% To assure parameter consistency, calling ratparam first below and

% commenting out redundant setting of parameters here.

% Paul Schlosser, U.S. EPA , 05-01-2013

ratparam

% VCHC=1.0E+9, KLOSS=0.0, DOSE=0,TINF=0.01,PDOSE=0 % set in ratparam

% CONCL=0, IVDOSE=0, TCHNG=999.0,TSTOP=120,CONCPPM=0,CONCMGM=0

% GDDAYS=6, SA=0.00001,DOSEINTERVAL=720

QUTRC=0.005, %QRAPC=0.512

 VLIVC=0.0366,VLUC=0.005,VFATC=0.09, %VRAPC=0.071, QLIVC= 0.183,

QPC=15,QCC=15, % These are both 16 in ratparam; PS 5-1-13

%QFATC=0.07,QSKNC=0.058 % set in ratparam

 % KM=234,VMAXC=21.8, KM2=48, VMAX2C=2.1 % set in ratparam

 BWINIT=0.235,GDDAYS=6, %GDMONTHS=0

 % KLC=3.9,KLNC=0.002, % set in ratparam

PAFC=0.1,NUMFET=7

NUMFET=14,PUPBW=5670 % Taken from pregparamsoutput.m

 %MAXT=1.0e-4

%MINT=1E-9,VUTRC=0.002,VMAMC = 0.01 % set in ratparam

%PAFC OF 0.1 IS NEAR MAX TRANSFER SEE GRAPHPAD PAF EFFECT 11 08
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 45

FIG_1_WELLS_1988_IV_PLASMA.M

%PROCED WELLS - IV

%WELLS AND DIGENIS 1988

prepare @all @clear

ratparam

DOSE=0,PDOSE=0,TCHNG=0.0083,TINF=0.0083,CINT=0.01

BWINIT=0.35, IVDOSE=45, TSTOP=24,GDDAYS=0

!!start/nc

MASBAL

% DATA WELLS (T,CV,Poet 2013 CV)

DWELLS = [0.08 90 65.59071

0.17 70 65.59071

0.25 60 64.07336

0.33 58 62.9852

0.50 56 60.90279

0.75 58 58.0206

1.00 52 55.2812

1.50 52 50.15439

2.0 50 45.45177

4.0 40 30.32493

6.0 35 19.94611

];

plot(_t, _cv, DWELLS(:,1), DWELLS(:,2), DWELLS(:,1), DWELLS(:,3),'Fig 2 Wells 1988 IV plasma.aps')
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 46

FIG_2_PAYAN_2002_IV_PLASMA.M

%PROCED WELLS - IV

%WELLS AND DIGENIS 1988

prepare @all @clear

ratparam

DOSE=0,PDOSE=0,TCHNG=0.0083,TINF=0.0083,CINT=0.01

BWINIT=0.35, IVDOSE=0.1, TSTOP=24,GDDAYS=1

!!start/nc

MASBAL

% DATA PAYAN (T,CV,Poet 2013 CV)

DPAYAN = [0.020.155 0.2573098

0.08 0.131 0.1561921

0.17 0.118 0.1433084

0.5 0.115 0.131193

1 0.112 0.1162329

1.5 0.109 0.1030575

2 0.103 0.09138391

3 0.093 0.07185712

4 0.06 0.05650498

];

plot(_t, _cv, DPAYAN(:,1), DPAYAN(:,2), DPAYAN(:,1), DPAYAN(:,3),'Fig 2 Payan 2002 IV plasma.aps')
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 47

FIG_3AB_PAYAN_2002_IV_5HNMP_PLASMA_URINE.M

prepare @all @clear

ratparam

% Commenting out items below set identicaly in ratparam; Paul Schlosser, U.S. EPA, 05-01-2013

%VCHC=1.0E+9, KLOSS=0.0, DOSE=0,TINF=0.01

 % CONCL=0, IVDOSE=0, 

TCHNG=0.01,TSTOP=78

 % GDDAYS=0, SA=0.00001,CONCPPM=0,CONCMGM=0

 BWINIT=0.25,CINT=0.1

 IVDOSE=0.1

 !!START /nc

 holdcvhp=[_t _cvhp];

 holdauhp=[_t _auhp];

 IVDOSE=1

!!START /nc

 holdcvhp=[holdcvhp _cvhp];

 holdauhp=[holdauhp _auhp];

IVDOSE=10

!!START /nc

 holdcvhp=[holdcvhp _cvhp];

 holdauhp=[holdauhp _auhp];

IVDOSE=100

!!START /nc

 holdcvhp=[holdcvhp _cvhp];

 holdauhp=[holdauhp _auhp];

IVDOSE=500,BWINIT=0.275

!!START /nc

 holdcvhp=[holdcvhp _cvhp];

 holdauhp=[holdauhp _auhp];

% DATA p5HNMP (T,CVHP,Poet 2013 CVHP)

p5HNMP = [0.01 0.000182 0.001615 0.015095 0.099633 0.207601

5 0.042203 0.422267 4.237931 39.48625 109.9071

10 0.02516 0.252532 2.613575 31.12196 133.5288

20 0.004531 0.045548 0.478971 7.101832 69.10229

30 0.000617 0.006203 0.065172 0.993501 15.54205

40 0.0000752 0.000756 0.007927 0.119737 2.215258

50 0.00000867 0.000087 0.000911 0.013623 0.27038
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 48

60 0.000000966 0.00000969 0.000101 0.001503 0.031528

70 0.000000105 0.00000106 0.000011 0.000163 0.0036

];

% DATA u5HNMP (T,AUHP,Poet 2013 AUHP)

u5HNMP = [0.01 1.19E-08 0.00000009 0.00000084 0.00000606 0.0000154

5 0.003922 0.039152 0.384723 3.146931 8.153724

10 0.008028 0.08031 0.804688 7.576738 24.42693

20 0.011128 0.111449 1.130311 11.91568 52.64661

30 0.011648 0.116677 1.185414 12.75838 63.2357

40 0.011719 0.117399 1.19301 12.87606 65.35392

50 0.011729 0.11749 1.193972 12.89082 65.65677

60 0.01173 0.117501 1.194088 12.89259 65.6955

70 0.01173 0.117503 1.194102 12.8928 65.70028

];

% DATA payanPlas (T,CVHP,Payan 2002 CVHP)

payanplas = [1 0.00061 NaN NaN NaN NaN

1.5 0.00055 NaN NaN NaN NaN

2 0.00161 NaN NaN NaN NaN

3 0.00398 NaN NaN NaN NaN

4 0.0251 0.376 3.28 NaN NaN

6 0.0341 NaN NaN NaN NaN

8 0.0187 NaN NaN 23.5 NaN

10 0.0095 NaN NaN NaN NaN

24 0.00007 NaN NaN NaN 46.9

];

% DATA payanUrin (T,AUHP,Payan 2002 AUHP)

payanurin = [4 0.0009 0.0153 0.164 0.725 4.83

8 0.005 0.0507 0.591 2.473 10.29

24 0.0123 0.1213 1.27 13.62 54.77

48 0.0127 0.12608 1.29 12.22 63.94

72 0.0128 0.12742 1.298 12.35 64.38

];

plot(holdcvhp(:,1),holdcvhp(:,2:6),p5HNMP(:,1), p5HNMP (:,2:6),payanplas(:,1), payanplas (:,2:6), 'Fig 2 

Payan 2002 IV plasma 5HNMP.aps')

plot(holdauhp(:,1),holdauhp(:,2:6),u5HNMP(:,1), u5HNMP (:,2:6),payanurin(:,1), payanurin (:,2:6), 'Fig 2 

Payan 2002 IV urine 5HNMP.aps')
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 49

FIG_4_PAYAN_2003_DERMAL_PLASMA.M

prepare @all @clear

%ratparams

ratparam % Added by Paul Schlosser (PS), U.S. EPA, to assure parameter consistency; 05-01-2013

%preg_rat_params

%payan dermal exposures: Payan et al. DMD 03

 % DOSE=0,PDOSE=0, % Commented out, PS 5-1-13

TCHNG=72,TSTOP=54, SA=10,VLIQ=200e-6

BWinit=0.250 % BWinit was 0.275; reset from Poet 5-16-13 Payenderm.m; PS 5-17-13

% CONCL=1030, FAD=0.76,PSK=150 %FAD - urine+carcas+tissues

CONCL=1050000, CINT=0.5 % from Poet 5-16-13 Payenderm.m; PS 5-17-13

% PSK and FAD (now) set in ratparam to assure cosnsitency; PS 5-1-13

%KPL=4.3e-3 % Moved to ratparam file, PS 5-1-13

 !!START /nc

holdauhp=[_t _auhp];

holdaunp=[_t _aunp];

holdca=[_t _cv];

holdch=[_t _cvhp];

holdcsurf=[_t _csurf];

% Commenting out of following lines based on Poet 5-16-13 Payenderm.m; PS 5-17-13

%BWinit=0.275,CONCL=1030,VLIQ=0.000400

% !!START /nc

% holdauhp=[holdauhp _auhp];

%holdaunp=[holdaunp _aunp];

%holdca=[holdca _cv];

%holdch=[holdch _cvhp];

%holdcsurf=[holdcsurf _csurf];

MASBAL

% DATA pNMP (T,Payan 2013 CV)

pNMP = [0.5 128.652

2.5 424.496

5 532.623

7.5 508.955

10 434.405

12.5 346.867

15 263.728

17.5 192.406

20 179.829

22.5 99.759

25 63.993

27.5 34.099

30 17.645

32.5 8.97

35 4.516
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 50

37.5 2.262

40 1.13

42.5 0.564

45 0.282

47.5 0.141

50 0.0701

50.5 0.061

51 0.0531

51.5 0.0462

52 0.0402

52.5 0.035

55 0.0175

57.5 0.00874

60 0.00437

];

% DATA PAYAN (T,Payan 2003 CVHP)

PAYAN = [0.51 160

0.87 260

1.6 330

1.84 410

2.57 440

2.81 490

3.18 510

3.78 550

4.63 540

5.85 540

7.8 530

9.74 490

23.7 100

25.7 110

29.9 60

47.9 0

54.2 0

];

%plot(holdcsurf(:,1),holdcsurf(:,2), 'figcsurf.aps')

%plot(holdauhp(:,1),holdauhp(:,2), 'figDERMALAUHP.aps')

%plot(holdaunp(:,1),holdaunp(:,2), 'figDERMALAUnP.aps')

plot(holdca(:,1),holdca(:,2), pNMP(:,1), pNMP (:,2),PAYAN (:,1), PAYAN (:,2), 'Fig 7 Payan 2003 Dermal 

plasma.aps')

%plot(holdch(:,1),holdch(:,2), 'figDERMALplasmahp.aps')
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 51

HUMAN_PARAMS.M

WESITG=0; WEDITG=0;

SRATE=0; RESLVL=[zeros(1,1441) (0:1440)]';

QPC = 15;

QLIVC = 0.25;

QSKC = 0.058;

BWINIT = 58;

VFATC = 0.23;

VRAPC = 0.042;

P = 0.0036;

HT = 180;

KAS = 1.36;

ICFAT = 0;

ICSKN = 0;

CONCMGM = 0;

PDOSE2= 0;

TCHNG = 8;

S2 = 0; P2 = 8;

S3 = 6720; P3 = 6720; ON3=0;

DENSITY = 1.03; VLIQ = 1.00e-99; BRUSH=0;

STARTDS = 0;

FRACIN = 1;

TIME1 = 8;

REPTM = 24;

NSTP = 10;

QCC = 15;

QMAMC = 0.027;

QUTRC = 0.005;

VALVC = 0.0079;

VLIVC = 0.031;

VUTRC = 0.0014;

PV = 32;

MW = 99.13;

KM2 = 50.5;

VMAX2C = 5.9;

VMAXC = 125;

KM = 151;

KME = 80.8;

VMXNEC = 0.011;

KMNE = 2.46;

VMAXEC = 7.3;

ICLIV = 0;

ICSLW = 0;

IVDOSE = 0;

PDOSE3= 0;

DAYSWK = 1; % Days per week of exposure, eg 5 for workplace; PMS 8-28-13

CONCL = 0;
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 52

RESID = 0;

TSTOP = 24;

FRACOR = 0.68;

TIME2 = 6720;

CINT = 0.1;

MAXT = 0.001;

QFATC = 0.05;

QRAPC = 0.48;

PAFC = 0.1;

VBLC = 0.06;

VMAMC = 0.0062;

VSKC = 0.051;

SAL = 0.0001;

SAV = 6700;

MW1 = 116.14;

ICRAP = 0;

CONCPPM = 0;

PDOSE = 0;

PDRINK = 0;

TMAX = 24;

PVL=2.7e-3; % Added per Poet 5-16-13 human_params.m; Paul Schlosser, U.S. EPA (PMS), 5-17-13

% DOSEINTERVAL = 24; % Not used, PMS 8-28-13

DOSEINT=999;

CINTC = 0.1;

TIME = 0;

TIME3 = 6720;

IALG = 2;

MINT = 1.00e-09;

PB = 450;

PMAM = 1;

PSLW = 0.77;

PSKL = 0.42 % Rat skin:saline, PMS 8-28-13

PSKB = 0.099 % (Rat skin:saline)/(human blood:saline), PMS 8-28-13

PSKA = 44.5 %use (blood/air)*(rat skin:liquid)/(human blood:liquid), PMS 8-28-13

% PSKA = 450 %750; Changed per Poet 5-16-13 human_params.m; PMS 5-17-13

PBHNP = 0;

PLIV = 0.82;

PRAP = 0.94;

PLIV1 = 2.5;

PRAP1 = 6.5;

ICART = 0;

PSLW1 = 0.08;

PFAT = 0.49;

PPLA = 0.31;

PUTR = 0.1;

PLU = 0.1;

PB1 = 1;

PFAT1 = 0.23;
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 53

%FAD=0.000001

FAD = 1 % Value used in Poet 5-16-13 BADER_DRM.m and AkkesDerm.m; PMS 5-17-13

%DERM=0 % Not used in Poet 5-16-13 'HumPregRetreive Restored 1.csl'; PMS 5-17-13

VCHC=1.0e+9; KLOSS=0.0; % From human simulation scripts; use as default for human; PMS 8-28-13

start @nocallback
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 54

POET_2013_FIG_5_AND_6.M

human_params

P2=3; S3=3.169; P3=3; ON3=1; DAYSWK=1;

BWINIT=79; HT=180; TSTOP=48;

% Poet 2013 Inhalation plasma NMP (T, 80mg CVEN, 39mg CVEN, 9.7 mg CVEN)

PLAS_NMP = [1 0.683103 0.332836 0.082749

2 1.024672 0.499001 0.12401

4 1.378491 0.670665 0.166542

6 1.661011 0.807381 0.200346

8 0.870433 0.422351 0.104658

10 0.476452 0.230971 0.057195

12 0.260598 0.126264 0.031254

14 0.14247 0.069009 0.017078

16 0.077869 0.037711 0.009332

18 0.045205 0.02189 0.005416

20 0.024702 0.011961 0.002959

];

% Poet 2013 Inhalation plasma NMP (T, 80mg CVEN1, 39mg CVEN1, 9.7 mg CVEN1)

PLAS_5HNMP = [1 0.24528 0.119668 0.02978

2 0.654421 0.319214 0.079424

4 1.63541 0.796202 0.197813

6 2.698992 1.309727 0.324586

8 3.13353 1.511975 0.373107

10 2.989524 1.433702 0.352195

12 2.622757 1.250767 0.306007

14 2.196787 1.042511 0.25417

16 1.78852 0.845258 0.205485

18 1.42952 0.673285 0.163293

20 1.128456 0.530008 0.128301

30 0.316655 0.147623 0.035559

40 0.084532 0.039321 0.009458

];

% Poet 2013 Inhalation plasma NMP (T, 80mg AUNP, 39mg AUNP, 9.7 mg AUNP)

URIN_NMP = [1 0.062401 0.038817 0.012091

2 0.152052 0.100311 0.033677

4 0.322807 0.223295 0.080098

6 0.538127 0.383801 0.144246

8 0.70041 0.501467 0.189331

10 0.83527 0.588113 0.217245

12 0.923142 0.638799 0.231732

14 0.97874 0.668416 0.239602

16 1.006836 0.682649 0.243234

18 1.019841 0.68907 0.244841

20 1.026145 0.692145 0.245604

30 1.031765 0.694865 0.246275
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 55

40 1.031889 0.694925 0.24629

];

% Poet 2013 Inhalation urine 5HNMP (T, 80mg AUHP, 39mg AUHP, 9.7 mg AUHP)

URIN_5HNMP = [1 0.275716 0.134652 0.033533

2 1.463359 0.715887 0.178497

4 6.268797 3.0758 0.768508

6 16.61853 8.177778 2.047459

8 16.61853 8.177778 2.047459

10 41.92996 20.65742 5.175538

12 54.71574 26.91465 6.735197

14 66.35912 32.57506 8.13928

16 76.81064 37.62227 9.385295

18 84.24161 41.1902 10.26256

20 90.03312 43.95864 10.94115

30 103.9081 50.54583 12.54824

40 107.083 52.04393 12.91223

];

% Hannover Inhalation plasma NMP (T, 80mg CVEN, 39mg CVEN, 9.7 mg CVEN)

H_PLAS_NMP = [3.096 0.954 3.292 0.458 3.29 0.17

6.241 1.517 6.153 0.649 6.29 0.29

7.358 0.938 7.337 0.417 7.29 0.18

8.251 0.719 8.38 0.361 8.29 0.14

10.11 0.505 10.14 0.258 10.29 0.13

24.358 0.088 24.551 0.027 24.81 0.04

48.641 0.005 47.273 0.017 NaN NaN

];

% Hannover Inhalation plasma NMP (T, 80mg CVEN1, 39mg CVEN1, 9.7 mg CVEN1)

H_PLAS_5HNMP = [3.096 1.44 3.292 0.688 3.29 0.21

6.241 2.94 6.153 1.425 6.29 0.39

7.358 3.19 7.337 1.488 7.29 0.39

8.251 3.14 8.38 1.463 8.29 0.36

10.11 2.91 10.14 1.35 10.29 0.36

24.358 0.61 24.551 0.238 NaN NaN

];

% Hannover Inhalation plasma NMP (T, 80mg AUNP, 39mg AUNP, 9.7 mg AUNP)

H_URIN_NMP = [3.096 0.23 3.292 0.132 3.29 0.08

7.358 0.67 7.337 0.339 7.29 0.16

10.11 0.86 10.14 0.512 10.29 0.2

24.358 1.03 24.551 0.565 24.81 0.26

48.641 1.07 47.273 0.599 48.37 0.26

];

% Hannover Inhalation urine 5HNMP (T, 80mg AUHP, 39mg AUHP, 9.7 mg AUHP)

H_URIN_5HNMP = [3.096 5.74 3.292 3.72 3.29 2.51

7.358 22.84 7.337 10.81 7.29 5.73
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 56

10.11 50.47 10.14 22.22 10.29 8.75

24.358 89.36 24.551 45.11 24.81 18.36

48.641 99.25 47.273 48.87 48.37 20.51

];

prepare @clear T CVEN CVEN1 AUNP AUHP

CONCMGM=80, start @nocallback

 holdcv=[_t _cven];

 holdcvhp=[_t _cven1];

 holdaunp=[_t _aunp];

 holdauhp=[_t _auhp];

for CONCMGM=[39 9.7]

start @nocallback

 holdcv=[holdcv _cven];

 holdcvhp=[holdcvhp _cven1];

 holdaunp=[holdaunp _aunp];

 holdauhp=[holdauhp _auhp];

end

plot(holdcv(:,1),holdcv(:,2:4), PLAS_NMP(:,1), PLAS_NMP(:,2:4),H_PLAS_NMP(:,1), 

H_PLAS_NMP(:,2),H_PLAS_NMP(:,3), H_PLAS_NMP(:,4),H_PLAS_NMP(:,5), H_PLAS_NMP(:,6),'Poet 2013 

Fig 4 Hannover plasma NMP.APS')

plot(holdcvhp(:,1),holdcvhp(:,2:4),PLAS_5HNMP(:,1), 

PLAS_5HNMP(:,2:4),H_PLAS_5HNMP(:,1),H_PLAS_5HNMP(:,2),H_PLAS_NMP(:,3), 

H_PLAS_5HNMP(:,4),H_PLAS_5HNMP(:,5), H_PLAS_5HNMP(:,6),'Poet 2013 Fig 4 Hannover plasma 

5HNMP.APS')

plot(holdaunp(:,1),holdaunp(:,2:4),URIN_NMP(:,1), URIN_NMP(:,2:4),H_URIN_NMP(:,1), 

H_URIN_NMP(:,2),H_URIN_NMP(:,3), H_URIN_NMP(:,4),H_URIN_NMP(:,5), H_URIN_NMP(:,6),'Poet 

2013 Fig 4 Hannover urine NMP.APS')

plot(holdauhp(:,1),holdauhp(:,2:4),URIN_5HNMP(:,1), URIN_5HNMP(:,2:4),H_URIN_5HNMP(:,1), 

H_URIN_5HNMP(:,2),H_URIN_5HNMP(:,3), H_URIN_5HNMP(:,4),H_URIN_5HNMP(:,5), 

H_URIN_5HNMP(:,6),'Poet 2013 Fig 4 Hannover urine 5HNMP.APS')
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 57

POET_2013_FIG_7_PLASMA.M

human_params

P2=8; SA=7500; BWINIT=75; HT=178.5; TSTOP=72

QPC=40,QCC=23,QSKC=0.18 %Andersen et al '87 as work, CORLEY ET AL

% Poet 2013 Inhalation plasma NMP (T, 53mg CVEN, 24mg CVEN, 10mg CVEN)

PLAS_NMP = [1 0.164826 0.395742 0.874626

2 0.246282 0.591566 1.30846

4 0.344082 0.827175 1.832502

6 0.392776 0.944901 2.096089

8 0.416782 1.003176 2.228192

10 0.182521 0.439988 0.979863

12 0.090665 0.218696 0.487648

14 0.045029 0.10865 0.242425

16 0.022361 0.053964 0.120446

18 0.011104 0.026799 0.059824

20 0.005514 0.013307 0.029709

22 0.002738 0.006608 0.014753

24 0.001359 0.003281 0.007326

];

% Akesson adn Paulsson Inhalation plasma NMP (T, 80mg CVEN, 39mg CVEN, 9.7 mg CVEN)

AP_PLAS_NMP = [4 0.3 0.99 1.6

8 0.49 0.82 2.6

9 0.3 0.72 2

10 0.22 0.51 1.28

12 0.12 0.3 0.75

16 0.08 0.2 0.3

24 0.03 0.06 0.08

32 0.01 0.02 0.03

48 0.01 0.01 0.02

];

prepare @clear T CVEN CVEN1 AUNP AUHP

CONCMGM=53; start @nocallback

 holdcv=[_t _cven];

 holdcvhp=[_t _cven1];

 holdaunp=[_t _aunp];

 holdauhp=[_t _auhp];

for CONCMGM=[24 10]

start @nocallback

holdcv=[holdcv _cven];

holdcvhp=[holdcvhp _cven1];

holdaunp=[holdaunp _aunp];

holdauhp=[holdauhp _auhp];

end
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 58

plot(holdcv(:,1),holdcv(:,2:4),PLAS_NMP(:,1),PLAS_NMP(:,[4 3 2]),AP_PLAS_NMP(:,1), AP_PLAS_NMP(:,[4 

3 2]), 'Poet 2013 Fig 5 Akesson and Paulsson plasma')

%plot(holdcvhp(:,1),holdcvhp(:,2:4),'FIGAKinhalcvhp.APS')

%plot(holdauhp(:,1),holdauhp(:,2:4), 'FIGAKinhalaunp.APS')

%plot(holdaunp(:,1),holdaunp(:,2:4),'FIGAKinhalauhp.APS')
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 59

POET_2013_FIG 8AB_PLASMA_&_URINE.M

human_params % Uncommented to assure consistent parameters; Paul Schlosser, U.S. EPA (PS), 5-17-

2013

SAL=5; SAV=1e-4; BWINIT=67.5; HT=160.0; %Wikipedia - German men weight 82.4 kg, women weigh 

67.5kg)

CONCL=1045000; VLIQ=0.0003; BRUSH=1; TSTOP=48; P2=6; WKDAYS=1; CINTC=0.1;

%FAD=1 %most was recovered on pad - 18.6 is "lost" to system. 

% FAD set in human_params.m, PS 5-17-13

%PV=0 % Intrinsic property for skin-air transport should not change from that set in human_params.m ...

% Since air concentration(s) are set to zero, this should not need to be zeroed 

here; PS 5-17-13

% Allowing PV=32 (default value) reduces predicted NMP and 5-HNMP by ~ 6% vs. PV = 

0; PS 5-17-13

% PVL= 2.9e-003 % If PV=32, this value of PVL gives nearly the same 'cvhp' and 'auhp' simulations; PS 5-

17-13

% Poet 2013 Dermal sims plasma NMP: 0.3 ml NMP applied)

PLAS_NMP = [2 0.2704 0.2170

4 0.6709 0.5418

6 1.050 0.8547

8 1.1445 0.9437

10 1.0497 0.8795

12 0.8898 0.7581

14 0.7220 0.6256

16 0.5704 0.5026

18 0.5635 0.4968

20 0.3401 0.3095

22 0.2590 0.2395

24 0.1962 0.1843

30 0.0837 0.0822

40 0.0197 0.0208

];

% Poet 2013 Dermal sims urine NMP: 0.3 ml NMP applied)

URIN_NMP = [2 0.4701 0.4381

4 2.4293 2.2716

6 6.0414 5.6806

8 10.7190 10.1404

10 15.3381 14.6079

12 19.4052 18.6049

14 22.7817 21.9778

16 NaN 24.98211

18 27.6136 26.9195

20 29.2560 28.6418

22 30.5132 29.9812

24 31.4690 31.0154

30 33.1474 32.8825

40 34.0853 33.9834
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 60

];

% Akesson 2004 Dermal plasma NMP: 0.3 ml NMP applied)

A_PLAS_NMP = [1.01 0.22 0.07

1.94 0.66 0.49

4.06 1.15 0.85

5.83 1.01 1.03

7.95 1.01 0.97

12.1 0.58 0.73

24 0.18 0.14

30.1 0.07 0.04

47.9 0.02 0.01

];

% Akesson 2004 Dermal urine NMP: 0.3 ml NMP applied)

A_URIN_NMP = [1 0.610509 0.451446

3 5.998437 4.368267

5 13.64819 9.921695

7 21.16922 16.61523

9 26.72265 21.70894

11 30.84175 24.85343

14 36.38598 30.03908

20 41.33442 34.87718

27 42.67313 36.24163

39 42.87835 36.44023

];

prepare @clear T CVEN1 AUHP

% women

start @nocallback

 holdcvhp=[_t _cven1];

 holdauhp=[_t _auhp];

BWINIT=82.4; % men

start @nocallback

 holdcvhp=[holdcvhp _cven1];

 holdauhp=[holdauhp _auhp];

plot(holdcvhp(:,1),holdcvhp(:,2:3),PLAS_NMP(:,1), 

PLAS_NMP(:,2:3),A_PLAS_NMP(:,1),A_PLAS_NMP(:,2:3), 'Poet 2013 Fig 8 plasma.APS')

plot(holdauhp(:,1),holdauhp(:,2:3),URIN_NMP(:,1), 

URIN_NMP(:,2:3),A_URIN_NMP(:,1),A_URIN_NMP(:,2:3), 'Poet 2013 Fig 8 urine.APS')

%ADVL

%AUNP
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 61

POET_2013_FIG_9_PLASMA.M

human_params % Uncommented to assure consistent parameters; Paul Schlosser, U.S. EPA (PS), 5-17-

2013

 DOSE=0,PDOSE=0,TCHNG=4,DOSINTERVAL=2.93,IVDOSE=0

CONCMGM=0,SAL=5, SAV=1e-4

CONCL=1045000,VLIQ=0.0003

 BWINIT=79, HT=160, TSTOP=48,TCHNG=6, BRUSH=1, P2=6, ON3=0

%FAD=1 %most was recovered on pad - 18.6 is "lost" to system. 

% FAD set in human_params.m, PS 5-17-13

PV=0 % Intrinsic property for skin-air transport should not change from that set in human_params.m ...

% Since air concentration(s) are set to zero, this should not need to be zeroed 

here; PS 5-17-13

% Allowing PV=32 (default value) reduces predicted NMP and 5-HNMP by ~ 6% vs. PV = 

0; PS 5-17-13

% PVL= 2.9e-003 % If PV=32, this value of PVL gives nearly the same 'cvhp' and 'auhp' simulations; PS 5-

17-13

% Poet 2013 Dermal sims plasma NMP: 0.3 ml NMP applied)

PLAS_NMP = [2 0.2527079

4 0.4365436

6 0.512324

8 0.338109

10 0.1865714

12 0.1029197

14 0.05676336

16 0.03130336

18 0.01726188

20 0.009518544

22 0.00524862

24 0.002894112

30 0.000485194

40 0.000024731

];

% Akesson and Paulsson 1997 inhalation data 

AP_PLAS_NMP = [4 0.3

8 0.49

9 0.3

10 0.22

12 0.12

16 0.08

24 0.03

32 0.01

48 0.01

];
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 62

CINTC=0.1; prepare @clear T CVEN

!!START /NC

 holdcvnp=[_t _cven];

plot(holdcvnp(:,1),holdcvnp(:,2),PLAS_NMP(:,1),PLAS_NMP(:,2),AP_PLAS_NMP(:,1),AP_PLAS_NMP(:,2), 

'Poet 2013 Fig 9 plasma.APS')
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 63

APPENDIX B. Corrections and changes in the PBPK models for N-Methylpyrrolidone as 

described by Poet (2013) (revised by T. Poet from that described in Poet et al., 2010)

Rat PBPK Model

Oral Dosing

While oral exposure is not a route of con

Exposure control

Because both Becci et al. (1982) and Saillenfait et al. (2002) explicitly stated that the animal BWs were 

measured every 3rd day of gestation, and the dermal/oral doses were adjusted accordingly on those days 

(as BW increases during pregnancy), corresponding conditional (if/then) statements were added to the 

‘GAVD’ and ‘REAPPLY’ discrete blocks, to re-calculate the doses on those days.

The code for the dermal discrete blocks follows. ASK0 is the absolute amount applied on each day; DSK 

is the dose/kg BW. Because Becci et al. (1982) rubbed the material into the skin, it is assumed to be 

added directly into the skin compartment (ASK), rather than as a liquid on top. Hence the dose is given 

as an addition of ASK0 (mg/day applied) to ASK.

DISCRETE SKWASH ! PMS, 8-14-13

ASK = 0.0 ! Assume skin washing in Becci et al. (1982) removes all NMP from skin

if (DAYS.LT.15.0) SCHEDULE REAPPLY.AT.(T+DOSEINTERVAL-TWASH)

END

DISCRETE REAPPLY ! PMS, 8-14-13

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

ASK = ASK + ASKO

SCHEDULE SKWASH.AT.(T+TWASH)

END

Also, because Becci et al. (1982) washed the skin area exposed to dermal application at the end of a set 

time interval, a “SKWASH” discrete block was introduced at which time the amount in that patch of skin 

was assumed to be momentarily reduced to zero. During periods of dermal application, transport from the 

liquid to the skin was turned on using the pulse function, DZONE. After removal of the liquid it was 

assumed that NMP in the skin patch could volatilize into the otherwise clean air, with the rate defined by 

the same permeability constants, but using the skin:air partition coefficient.

The rate of transfer to/from the skin area is then defined by:

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

Finally, a constant, CONCMGS, was introduced so that the air concentration could be set directly in 

mg/m

3

. This is converted to the concentration in mg/L (CONCMG) in the code and added to the 
N-METHYLPYRROLIDONE PBPK Models EP-C-09-006 WA 4-01 September 11, 2013

Page 64

inhalation exposure, turned on and off using the switch, CIZONE, which is turned on and off using 

SCHEDULE/DISCRETE statements:

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

CIZONE*CONCMG, PMS, 8-13-13

Skin compartment

Corrections to the mass balance equations for the rat skin are as indicated in the commented code copied 

below. It includes the initial condition, ASK0, for the initial dermal application, but is otherwise now the 

standard format for PBPK models. As received the code had multiplied CSK rather than CSKV (skin 

venous blood concentration) by the blood flow (QSKN) for the rate of efflux in blood, and had not 

separately calculated CSKV.

RASK = QSKN*(CA - CSKV) + RADL ! NOW MINUS CSKV, NOT CSK; PMS 8-21-13

ASK = INTEG(RASK,ASKO) ! Initial value, ASKO, added for Becci et al. (1982) exposures; pms 

8-14-13

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

CSKV = CSK/PSKB ! NMP IN VENOUS BLOOD, PMS 8-22-13

The corresponding flow term for transfer from the skin to the mixed venous blood compartment was also 

corrected (ie, to use CVSK instead of CSK).

While these changes to the skin compartment equations initially degraded the fits to the dermal exposure 

considerably, it also appeared that the associated partition coefficients were not consistent with the 

measured values reported by Poet et al. (2010), Table 5. They were recalculated as follows:

Skin:liquid, PSKL = 0.42: value as measured for skin:saline, vs. 450

Skin:blood, PSKB = 0.12: (skin:saline)/(blood:saline)

Skin:air, PSKA = 55: (skin:saline)*(blood:air)/(blood:saline) = (skin:blood)*(blood:air)

Blood flows

Since the placenta is a separate compartment for the 5HNMP compartment, its blood-flow and volume 

were removed from the sums used for the ‘rest of body’ for 5HNMP. Also, the term for blood flow from 

the placenta was added to the mixed-venous blood mass balance for 5HNMP.

To assure flow mass balance, instead of calculating cardiac output (QC) as an initial amount plus the 

change from initial for each compartment, it was just calculated as the sum over all the compartments:

! QC = QCINIT + (QFAT - QFATI) + (QMAM - QMAMI) + QPLA+ (QUTR - QUTRI)

QC = QFAT+QLIV+QSLW+QRAP+QSKN+QMAM+QPLA+QUTR ! pms, 8-13-13

Parameter Consolidation

In the provided files, some physiological and chemical-specific parameter were set in separate scripts; 

e.g., skin transport parameters in the dermal exposure scripts. This approach creates the potential for 

inconsistent parameters between different exposure simulations. Therefore all parameters are now set in 

the ratparam.m script except those which are experimental control variables (eg., air concentration, 
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duration of exposure). The final set of parameters used and any inconsistencies with previous values in 

ratparam.m that may have differed are noted in that script.

Human PBPK Model

Exposure and Timing Control

A table function, RESLVL, was added as a place-holder for reading in defined (residential) inhalation 

exposure time-courses; specifically from U.S. EPA exposure assessment modeling.

A constant, GDstart, the day of gestation on which the simulation starts, and a variable Gtime, the hours 

into gestation, were added to facilitate separating exposure control from gestation timing.

A second set of DISCRETE/SCHEDULE blocks were added to allow for split exposure scenarios 

(morning/afternoon worker exposure; dual-episode residential exposures).

DZONE, set in the DISCRETE/SCHEDULE blocks, controls the time within a day when discontinuous 

exposure occurs. Czone is the product of DZONE and a pulse function used to control for days/week 

exposure in workplace scenarios:

Czone = pulse(0.0,fullweek,hrsweek)*DZONE ! pms 8-20-13

! for a 5 day/wk exposure, use fullweek=7*24, hrsweek=5*24 (Dayswk=5)

! for a single day, fullweek=1e16, hrsweek=24 (Dayswk=1)

A binary constant, BRUSH, was added to set when dermal contact with liquid occurs. The rate for 

delivery from a liquid film to the ‘SKL’ skin compartment (also see further below) is then defined by:

RASL=(PVL*SAL/1000.0)*(CSURF-(CSKL/PSKL))*Czone*BRUSH

A constant SRATE was added for the net rate of delivery by liquid droplets to the skin for workplace 

spray applications. This is a net rate delivered into the skin compartment, rather than a liquid layer on the 

surface, assuming that the exposure modeling already accounts for material that may be temporarily 

deposited on the surface but not absorbed. (Absorption from a liquid layer of a defined (possibly 

changing) concentration was retained for other exposure scenarios, including residential.) When spray 

delivery SRATE is non-zero, concentration-driven transport from liquid or vapor is turned off for the 

spray/liquid exposed skin. The equations for transfer of vapor (air concentration = CI) to the SKL 

compartment, which occurs during periods with no liquid/spray contact, and/or spray absorption for the 

SKL compartment are then:

Sdeliv = SRATE*Czone ! Constant-rate spray delivery; pms 8-20-13

! Spray-dermal exposures, assumed simultaneous with inhalation (unless FRACIN = 0)

RADVL = (PV*SAL/1000.0)*(CI - (CSKL/PSKA))*(1.0-Czone*BRUSH)*(Sdeliv.eq.0.0) + Sdeliv

! RADVL allows absorption/desorption from air when there is NOT spray or

! brushing dermal exposure, when both sdeliv and czone are zero; pms 8-20-13
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Skin compartment

As for the rat, and noted in the main report, corrections were made to the human skin transport and PK 

(equations not shown here, but same as for rat). The partition coefficients were also recalculated as was 

done for the rat, with rat parameters for skin:saline and blood:air, but human blood:saline.

The original skin compartment which is coded to include uptake from liquid-dermal contact was renamed 

by adding “L” to the end, SK  SKL, and second skin compartment to account for concurrent vapor-skin 

uptake, SKV, was added. This was done because when the human model was calibrated for inhalation 

exposure, an exposed skin surface area of 6700 cm2 was used. When this surface are is reduced to ~ 0, 

predicted blood levels of NMP shown in the upper panel of Figure 4 in the QA report are reduced ~ 45%. 

Thus vapor uptake through the skin is a significant component of inhalation exposure and there is no 

reason to assume, a priori, that this uptake does not occur through a similar area of exposed skin during 

workplace and residential exposures, except for any area that would have liquid contact or otherwise be 

occluded (e.g., by wearing rubber gloves). So the SKV compartment allows for simultaneous absorption 

of vapor through skin that does not have liquid contact, and from areas of skin with liquid contact. The 

surface area of SKV and SKL are SAV and SAL, respectively, and can be set for different exposure 

scenarios. For EPA simulations, SAV was reduced from 6700 cm2by the area assumed to have liquid 

contact or covered by gloves for those scenarios. To evaluate the impact of this assumption for workplace 

exposure simulations were also conducted with SAV set to 0.01 cm2for a low rate of dermal delivery 

(600 mg/day).

Tissue and blood-flow mass balances

The model had been previously coded with an alveolar blood compartment (ALV), but this was 

commented out by the author in the DYNAMIC section. Therefore this volume fraction should not be 

subtracted when calculating the slowly-perfused volume. The fraction of blood-flow to slowly perfused 

tissue was updated to also account for the SKV compartment; on the other hand a separate skin 

compartment is not used for 5HNMP, so the skin blood flow is NOT subtracted for the metabolite-slowlyperfused compartment (SLW5). These have all been corrected.

QSKCC (original fractional flow to the skin) had been subtracted twice, both in calculating QSLWC and 

then in the calculation of QSLW. The 2nd subtracted created a mass balance error and hence was 

removed. On the other hand, placental blood flow is now subtracted, so the total flow to slowly-perfused 

continues to total cardiac output minus all other tissue/group flows.

For tissues that change with gestation day, the initial values were corrected to match the calculation in the 

DYNAMIC section, which would apply at the first time-step.

In the dynamic section, the calculation of QC was corrected to include the *increase* in placental flow 

(QPLA – QPLAI) rather than the total placental flow (QPLA), since QCINIT includes QPLAI. QSLW5 

and VSLW5 (5HNMP slow compartment flow and volume) are now calculated in the DYNAMIC section 

by subtraction.

Oral absorption parameters and equations

The oral absorption rate as a function of the amount in the stomach lumen compartment, AO, had been 

erroneously written as, RAO = KAS*FRACOR*AO, with the initial amount in the compartment set to be 
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the total administered dose, ODOSE. Since there is no other route of clearance from the stomach lumen 

compartment, this approach only reduces the effective absorption rate constant from KAS to 

KAS*FRACOR without reducing the total amount absorbed. Using the code as provided and the 

parameters for absorption listed in Poet et al. (2010) gives a significant over-prediction of the plasma 

NMP levels, not consistent with the simulations shown in Fig. 5 of Poet et al. (2010), which appear to fit 

those data well. Therefore the code was corrected to make 

ODOSE = FRACOR*DOSE*BWINIT

(instead of DOSE*BWINIT) and 

RAO = KAS*AO.

When this was done the AUC for plasma NMP appeared to be approximately correct, but the initial rise 

vs. time was faster and the peak occurred earlier than shown in Fig. 5 of Poet et al. (2010). When KAS 

was then reduced by FRACOR (68%), the model simulations shown in the preface for this report were 

obtained. The simulations for plasma NMP are quite close to those shown in Figure 5 of Poet et al. 

(2010) and fit the data fairly well. Therefore it is assumed that the results of Poet et al. (2010) included

the multiplication by FRACOR in computing RAO, but also reduced the oral dose by FRACOR. The 

U.S. EA version uses the corrected equations shown just above, to deconvolute the two parameters 

(FRACOR and KAS) and allow DOSE to simply be set to the applied dose.

Parameter Consolidation

As for the rat model, the human model physiological and biochemical parameters are now all set in a 

single script, human_params.m. Only constants which define specific exposure scenarios (include skin 

areas exposed) are defined in the specific simulation scripts.