Route-to-Route Extrapolation of 1,1,2-Trichloroethane Studies

from the Oral Route to Inhalation Using Physiologically Based

Pharmacokinetic Models:

Acute Neurotoxicity

Prepared for

HAP Task Force, Millwood, Virginia

Prepared by

The Sapphire Group, Dayton, Ohio

November 29, 2004
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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EXECUTIVE SUMMARY

A need has been identified for a quantitative understanding of the hazards of 1,1,2-

trichloroethane (1,1,2-TCE) exposure by the inhalation route. Under Section 4 of the Toxic

Substances Control Act (TSCA), the U.S. EPA issued a testing consent order (Enforceable

Consent Agreement, ECA) to perform toxicity testing and mechanistic and pharmacokinetic

studies to satisfy EPA’s data needs for 1,1,2-TCE (U.S. EPA, 2000, 2003a). As part of Tier

I testing, pharmacokinetic studies were conducted (Poet et al., 2003) and a physiologically

based pharmacokinetic (PBPK) model was developed that describes the disposition of 1,1,2-

TCE by oral and inhalation routes (The Sapphire Group, 2003). 

This report serves to fulfill the identified data need for route-to-route extrapolation of results

of acute neurotoxicity studies conducted by the oral route to the inhalation route. The routeto-route extrapolation of results of the 1,1,2-TCE acute neurotoxicity test using the PBPK

model was based on selection of a critical endpoint (gait impairment), the most appropriate

internal dose measures, and an appropriate point of departure. It is our opinion that the most

appropriate dose metric for route to route extrapolation is the peak concentration of 1,1,2-

TCE in the brain. Route-to-route extrapolation results for other ECA-specified endpoints are

provided as an appendix. The appropriate point of departure was determined to be the

NOAEL for male and female rats. Based on PBPK modeling results, the rat acute

neurotoxicity NOAEL from gavage dosing (95 mg/kg) is equivalent to continuous (24-hour)

inhalation exposure of rats to 163 ppm 1,1,2-TCE. Sensitivity analysis of the rat route-toroute extrapolation results indicated that the equivalent inhalation exposure was sensitive to

several model parameter values, but most sensitive to the maximal rate of metabolism

(Vmaxc), ventilation rate (QPC), absorption rate (Ka), and the dose used as the basis for

extrapolation. 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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INTRODUCTION

Summary of Hazardous Air Pollutants (HAPs) Framework

1,1,2-Trichloroethane (1,1,2-TCE, CAS No. 79-00-5) is used as an intermediate in the

production of vinylidene chloride, as a solvent, in adhesives and lacquers, and in the

production of Teflon . A need has been identified for a quantitative understanding of the ®

hazards of 1,1,2-TCE exposure by the inhalation route. Under Section 4 of the Toxic

Substances Control Act (TSCA), the U.S. EPA issued a testing consent order (Enforceable

Consent Agreement, ECA) to perform toxicity testing and mechanistic and pharmacokinetic

studies to satisfy EPA’s data needs for 1,1,2-TCE (U.S. EPA, 2000) that was subsequently

modified with respect to timing and expands consideration of dose metrics for route

dosimetry extrapolations (U.S. EPA, 2003a).

Summary of Physiologically based Pharmacokinetic (PBPK) Model

The objective of a combination of experimental studies (Poet et al., 2003) and modeling (The

Sapphire Group, 2003) was to develop a physiologically based pharmacokinetic (PBPK)

model that would allow route-to-route extrapolation from existing and future data on hazards

of oral 1,1,2-TCE exposure to assess inhalation hazards. Models were developed for both

rats and mice (The Sapphire Group, 2003), but since only rats are relevant to interpretation

of the acute neurotoxicity study, results for mice are not discussed here. For PBPK model

development and refinement, female rats were exposed to 100 ppm 1,1,2-TCE for six

hours/day, five days/week for four weeks, with blood sampling on days one, three, and five

of week four. Additional groups of female rats received daily doses of 1,1,2-TCE by gavage

(water or corn oil vehicle) for five days, with blood sampling on days one, three, and five.

Target doses were 1.7 mg/kg in water and 92 mg/kg in corn oil for rats. 

The model is an expansion and refinement of the PBPK model for disposition of 1,1,2-TCE

in male F344 rats developed by Gargas et al. (1989) based on exhaled breath data following

inhalation exposure. The expanded model includes a spleen (to permit dosimetry

calculations for this tissue for the immunotoxicity endpoints, U.S. EPA, 2000, 2003a) and

can be used to calculate specified dose metrics of interest (blood concentrations, tissue

concentrations, or amounts metabolized) after inhalation, gavage (corn oil or water), and

drinking water consumption. Model parameters determined by optimization (maximum

biotransformation rate, enzyme affinity, and absorption rates) provided an adequate fit to the

rat data sets. Model code is provided in Appendix A.
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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SUMMARY OF KEY STUDY

Study Design

A study to evaluate the acute neurotoxic potential of 1,1,2-TCE was conducted using

Crl:CD (SD) IGS BR rats. 1,1,2-TCE was administered in corn oil by gavage to 12 ®

animals/sex/dose, at a dose of 0, 55, 95, or 200 mg/kg on study day 0. Animals were

observed twice daily for mortality and moribundity; clinical examinations were performed

daily, and body weights were recorded weekly. Functional observational battery (FOB) and

locomotor activity data were recorded prior to dosing, at the estimated time of peak effect

(45 minutes post-dosing) on study day 0 and on study days 7 and 14. At euthanasia on study

day 15, brain weights (excluding olfactory bulb), and brain dimensions were recorded for all

animals. A neuropathological evaluation was performed on six animals/sex from the control

and 200 mg/kg groups (Beck, 2004). While the acute neurotoxicity study was conducted in

SD rats and the PBPK model was developed for F344 rats, it is unlikely that physiological

or metabolic differences will have a significant impact on the model’s ability to simulate the

disposition of 1,1,2-TCE in the test strain (Simmons et al., 2002; Schoeffner et al., 1999;

Wang et al., 2000). 

Study Results

At the time of peak effect, fewer male and female rats in the 200 mg/kg groups were found

with eyes wide open. Hypoactivity and disruption of habituation were observed in the 95 and

200 mg/kg groups of males and females in the study day 0 locomotor activity assessment.

Gait impairment and abnormal gait scores were identified in the FOB tests of the 200 mg/kg

groups on study day 0. The changes in neurobehavioral endpoints occurred in the absence

of neuropathology. The motor activity effects noted in the 95 mg/kg groups were not

considered adverse because of the lack of persistence and the lack of correlating FOB

findings. The NOAEL was thus defined as 95 mg/kg and LOAEL as 200 mg/kg (Beck,

2004).

SELECTION OF CRITICAL ENDPOINTS AND DOSE MEASURES

Critical Endpoint and Dose Measures

The critical endpoint, gait impairment, was identified in FOB testing of rats (Beck, 2004).

Parent compound in venous blood and brain (as Cmax and as AUC) and metabolite, as

amount metabolized in the liver or brain per day normalized to liver weight, were specified

as dose metrics in the amended ECA (U.S. EPA, 2003a). Consistent with USEPA’s Draft

Final Guidelines for Carcinogen Risk Assessment (U.S.EPA, 2003b), the selection of an
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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appropriate dose measure requires a careful consideration of the mode of action by which a

chemical exerts an effect (carcinogenic or otherwise). 

The observed effect, gait impairment, was found to be acute and transitory (Beck, 2004). A

wide variety of solvents are known to produce anesthetic or sedative effects in animals and

humans by altering nerve cell membrane properties (Snyder and Andrews, 1996). 1,1,2-

Trichloroethane may depress spontaneous and evoked activity of neurons in the brain,

possibly through non-specific actions with the lipid matrix of the nerve membrane or by a

mo Are specific action on the GABA receptor chloride channel, a major mediator of inhibitory

synaptic transmission (Trevor and White, 2004). A mode of action involving nerve cell ion

current modification by the parent chemical is consistent with observations made for a wide

variety of organic vapors and solvents (Richards et al., 1978; Pringle et al., 1981; Janoff and

Miller, 1982, Franks and Lieb, 1987; Chiou et al., 1990; Curry et al., 1990; Honma et al.,

1985; Janes et al., 1992; Messaoudi et al., 1992; Dickinson et al., 1993; Slater et al., 1993).

Thus, it is our opinion that the most appropriate dose metric for route to route extrapolation

is the peak concentration in the brain. 

ROUTE TO ROUTE EXTRAPOLATION RESULTS

Route-to-route extrapolations of the acute neurotoxicity NOAEL and LOAEL for rats were

performed using the PBPK model (The Sapphire Group, 2003). Results for the most

appropriate endpoint for the extrapolation, peak concentration of 1,1,2-TCE in the brain, are

reported below; results for other dose measures specified by the ECA are provided in

Appendix B. Graphical presentation of route-to-route extrapolation curves for rats are

presented in Appendix C. 

For male rats, based on equal peak concentrations of 1,1,2-TCE in the brain, the acute oral

neurotoxicity NOAEL of 95 mg/kg is equivalent to inhalation of 170 ppm 1,1,2-

trichloroethane, and the LOAEL of 200 mg/kg is equivalent to inhalation of 255 ppm. For

female rats, oral acute neurotoxicity NOAEL and LOAEL of 95 and 200 mg/kg are

equivalent to inhalation of 163 ppm and 244 ppm 1,1,2-trichloroethane, respectively. Since

the NOAEL inhalation equivalent concentration in female rats (163 ppm) is lower than that

determined for male rats (170 ppm), the female rat equivalent is recommended for

extrapolation and any risk assessment purposes. These results are consistent with findings

of previous studies of 1,1,2-TCE by the inhalation route. One study (Kirkpatrick, 2001)

reported evidence of acute neurotoxicity (ataxia) in rats exposed to concentrations at or

exceeding 840 ppm 1,1,2-TCE, but not in animals exposed to 58 or 181 ppm.
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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SENSITIVITY ANALYSIS

The sensitivity of the critical dose metric, peak concentration of 1,1,2-TCE in the rat brain,

to changes in model parameter values was evaluated for scenarios involving corn oil gavage

or continuous inhalation. In the gavage scenario, a dose of 95 mg/kg, the NOAEL, to female

rats was used as the basis of the analysis, and the continuous inhalation equivalent for female

rats, 163 ppm, was used as the basis of the inhalation sensitivity analysis. Sensitivity analysis

was conducted by increasing a parameter value by 1% and noting the change in the model

prediction of interest (peak concentration in the brain). The fractional increase in the

prediction divided by the fractional increase in the parameter was defined as the normalized

sensitivity coefficient. The results are summarized in Table 1.

Table 1.

Sensitivity of Predictions of Peak Brain Concentration to Model Parameter Values

Sensitivity Coefficient

Parameter Gavage Inhalation a b

Blood:air partition coefficient (PBA) -0.42 -0.35

Fat:air partition coefficient (PFA) -0.14 -0.03

Richly perfused tissues (RPT):air partition coefficient (PRA) -0.11 <0.05

Slowly perfused tissues:air partition coefficient (PSA) -0.11 <0.05

Brain:air partition coefficient (PBRA) 1.0 1.0

Maximum metabolism of 1,1,2-TCE (VmaxC) -0.91 -2.42

Michaelis constant for metabolism of 1,1,2-TCE (KM) 0.21 <0.05

Body weight (BW) 0.44 <0.05

Normalized alveolar ventilation rate (QPC) -0.18 2.67

Normalized cardiac output (QCC) -0.39 -0.14

Fractional blood flow to liver (QLC) <0.05 -0.15

Fractional blood flow to fat (QFC) -0.43 <0.05

Fractional volume of fat (VFC) -0.14 <0.05

Fractional volume of RPT (VRC) -0.11 <0.05

Fractional volume of SPT (VSC) -0.11 <0.05

Oral absorption rate from corn oil (KA) 1.47 NA

Dose (DOSE) 1.86 NA

Concentration (CONC) NA 3.30

All other parameters: |sensitivity coefficient| <0.05

Gavage dose of 95 mg/kg/ 1,1,2-TCE in corn oil to female rats a

Continuous inhalation exposure of female rats to 163 ppm 1,1,2-TCE. b
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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For the gavage and inhalation scenarios, the model predictions of peak brain concentration

were sensitive to several parameters, but most sensitive to dose/concentration, maximum rate

of metabolism, absorption rate, ventilation rate, and brain:air partition coefficient. The

sensitivity of the model predictions to the brain:air partition coefficient, however, do not

enter into determining the value of the inhalation-equivalent NOAEL because the

sensitivities are equal for the inhalation and oral routes.

CONCLUSIONS

The PBPK model-based route-to-route extrapolation of results of the 1,1,2-TCE acute

neurotoxicity study was based on selection of a critical endpoint, the most appropriate

internal dose measure, and an appropriate point of departure. The critical endpoint was gait

disturbance, as determined by Beck (2004). The most appropriate internal dose measure,

peak concentration of 1,1,2-TCE in the brain, was selected from dose measures specified in

the ECA based on likely mode of action. The female rat NOAEL of 95 mg/kg was

considered an appropriate basis for route-to-route extrapolation, resulting in an estimated

equivalent continuous inhalation exposure 163 ppm. Sensitivity analyses of the selected

internal dose measure to changes in model parameter values were conducted for gavage and

inhalation scenarios. At doses/concentrations relevant to the route-to-route extrapolation, the

model predictions of peak concentrations in the brain were sensitive to several parameters.

We recommend that continuous (24-hour) inhalation exposure of rats to 163 ppm 1,1,2-TCE

be considered equivalent to the rat NOAEL of 95 mg/kg-d for acute neurotoxic effects.
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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REFERENCES

Beck, M.J. (2004). An acute neurotoxicity study of 1,1,2-trichloroethane in rats. WIL-417-

004. Final report. September 10, 2004. WIL Research Laboratories, Ashland, Ohio.

Chiou, J. -S., Ma, S. -M., Kamaya, H. & Ueda, I. 1990. Anaesthesia cutoff phenomenon:

Interfacial hydrogen bonding. Science, 248: 583-585.

Curry, S., Lieb, W. R. & Franks, N. P. 1990. Effects of general anaesthetics on the bacterial

luciferase enzyme from Vibrio harveyi: An anaesthetic target site with differential sensitivity.

Biochem. 29: 4641-4652.

Dickinson, R., Franks, N. P. & Lieb, W. R. 1993. Thermodynamics of anaesthetic/protein

interactions. Temperature studies on firefly luciferase. Biophys. J. 64: 1264-1271.

Franks, N. P. & Lieb, W. R. 1994. Molecular and cellular mechanisms of general

anaesthesia. Nature, 367: 607-614.

Gargas, M. L. & Andersen, M. E. 1989. Determining kinetic constants of chlorinated ethane

metabolism in the rat from rates of exhalation. Toxicol Appl Pharmacol 99, 344-353.

Honma T, Miyagawa M, Sato M & Hasegawa H. 1985. Neurotoxicity and metabolism of

methyl bromide in rats. Toxicol Appl Pharmacol 81(2):183-91.

Janes, N., Hsu, J. W., Rubin, E. & Taraschi, T. F. 1992. Nature of alcohol and anæsthetic

action on cooperative membrane equilibria. Biochem. 31: 9467-9472

Janoff, A. S. & Miller, K. W. 1982. A critical assessment of the lipid theories of general

anaesthetic action. In: Biological Membranes. pp. 417-476. Chapman, D. Ed., Academic

Press, London.

Kirkpatrick, D. T. 2001. An acute inhalation toxicity (with histopathology) study of 1,1,2-

trichloroethane (1,1,2-TCE) in rats. WIL-417-001. Final report. October 29, 2001. WIL

Research Laboratories, Ashland, Ohio.

Messaoudi, S., Lee, K. -H., Beaulieu, D., Baribeau, J. & Boucher, F. 1992. Equilibria

between multiple spectral forms of bacteriorhodopsin effect of delipidation, anesthetics and

solvents on their pH dependance. Biochim. Biophys. Acta, 1140: 45-52.
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 9

Poet, T. S., Curry, T.L., Luders, T.M., Wu, H., Studniski, K. G., Weitz, K. K., & Corley, R.

A. 2003. Pharmacokinetics of 1,1,2-Trichloroethane in Rats and Mice. Battelle Project No.

41608. June 10, 2003. Amended Final Report. 

Pringle, M. J., Brown, K. B. & Miller, K. W. 1981. Can the lipid theories of anaesthesia

account for the cutoff in anaesthetic potency in homologous series of alcohols. Molecular

Pharmacol. 19: 49-55.

Richards, C. D., Martin, K., Gregory, S., Keightley, C. A., Hesketh, T. R., Smith, G. A.,

Warren, G. B. & Metcalfe, J. C. 1978. Degenerate perturbations of protein structure as the

mechanism of anaesthetic action. Nature, 276: 775-779.

Schoeffner DJ, Warren DA, Muralidara S, Bruckner JV, Simmons JE. 1999. Organ weights

and fat volume in rats as a function of strain and age.J Toxicol Environ Health A. 56: 449-62.

Simmons JE, Boyes WK, Bushnell PJ, Raymer JH, Limsakun T, McDonald A, Sey YM,

Evans MV. 2002. A physiologically based pharmacokinetic model for trichloroethylene in

the male long-evans rat. Toxicol Sci. 69: 3-15. 

Slater, S. J., Cox, K. J. A., Lombardi, J. V., Ho, C., Kelly, M. B., Rubin, E. & Stubbs, C. D.

1993. Inhibition of protein kinase C by alcohols and anaesthetics, Nature, 364: 82-84.

Snyder R. & Andrews L. S. 1996. Toxic Effects of Solvents and Vapors. In: Casarett and

Doull’s Toxicology The Basic Science of Poisons 5 edition. Ed CD Klasssen. McGraw-Hill th

New York.

The Sapphire Group. 2003. Physiologically Based Pharmacokinetic Model Development,

Simulations, and Sensitivity Analysis for Repeated Exposure to 1,1,2-Trichloroethane.

Revised final report. July 7, 2003, Dayton, Ohio.

U.S. EPA. 2000. 1,1,2-Trichloroethane (TCE); Final Enforceable Consent Agreement and

Testing Consent Order. Federal Register 65, No. 116, pp 37550-37553, June 15, 2000.

U.S. EPA. 2003a. 1,1,2-Trichloroethane (TCE); EPA Program Review: Notice of

Availability. Federal Register 68, No. 131, pp 40944-40947, July 9, 2003.

U.S. EPA. 2003b. Draft Final Guidelines for Carcinogen Risk Assessment.

NCEA-F-0644A. 03 Mar 2003. U.S. Environmental Protection Agency, Risk Assessment

Forum, Washington, DC, 125 pp.
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 10

Wang X, Santostefano MJ, DeVito MJ, Birnbaum LS. 2000. Extrapolation of a PBPK model

for dioxins across dosage regimen, gender, strain, and species. Toxicol Sci. 56: 49-60. 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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APPENDIX A

PBPK MODEL CODE

GISIR3.CMD

'File Name is GI.cmd, Rev 1/19/90 at 9:30 am'

'rev 5/1/01, 8/31/01 lms for 112tce only'

'rev 4/16-17/02 for sensitivity analysis, optimized values'

'rev 05/09/02 for reoptimized values'

'rev 071703 for rereoptimized values'

SET TJNITG = 1.0 $'Threshold for Jacobian Error Messages'

SET TSMITG = .T. $'Two sided matrix evaluation for increased accur.'

SET NSTP = 1000 $'Allow the integrator to take very small steps'

'SET PRN=7 ' $'Save output in SIMUSOLV.LOG file'

 

PREPAR T,PPMOUT,CA,CV,CL,CVL,AUCL,DM,AM,AUCB,AML,DM1,csn,aucsn,aucv

prepar cbr aucbr

PROCED MANY $ S NRWITG=.T.,FTSPLT=.T. $ END

PROCED ONE $ S NRWITG=.F. $ END

PROCED CCL2CCL $'1,1,2-TRICHLOROETHANE, X MG/KG gavage dose'

SET N=5

SET Flow=10700,vchc=2200, POINTS=240 

SET KA=2.0,KAI=0.,KSI=0.

SET DOSE=0.,TSTOP=2.

END

proced bolus

set drpct=1.0, 0, 0, 0, 0, 0

set drtime=0, 4, 8, 12, 16, 20

set tchng=120

end

proced perdwr

set drpct=0.233, 0.1, 0.1, 0.1, 0.233, 0.234

set drtime=0, 4, 8, 12, 16, 20

set tchng=99999

end

proced begin

ccl2ccl

mouse

set n=1, points=30000, tstop=168

set ka=0.2

end

PROCED MOUSE $'PHYSIOL FROM BROWN ET AL 1997'

 SET TITLE = ' 1,1,2-TCE FEMALE MOUSE' 

 SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1

 SET PSNA=43

 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.0
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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 SET BW=0.025,QPC=14,QCC=14

 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011

 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493

 SET VSNC=0.0035

 SET KDET=0.025, KDbi=0.0914

 set fnight=0.79, per1=0.5715, dur1=0.014, per2=1, dur2=0.016

 END $'of proced mouse' 

PROCED MMOUSE $'PHYSIOL FROM BROWN ET AL 1997'

 SET TITLE = ' 1,1,2-TCE MALE MOUSE' 

 SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1

 SET PSNA=43

 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.0

 SET BW=0.025,QPC=14,QCC=14

 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011

 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493

 SET VSNC=0.0035

 SET KDET=0.025, KDBI=0.0

 set fnight=0.79, per1=0.57, dur1=0.014, per2=1, dur2=0.016

 END $'of proced Mmouse' 

PROCED rat 

 SET TITLE = ' 1,1,2-TCE RAT' 

 SET MW=133.41,PB=58.,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1

 SET PSNA=43

 SET VMAXC=10.2,VMAXRC=0,KM=0.54,KFC=0.0

 SET BW=0.25,QPC=13,QCC=13

 SET QLC=0.183,QBRC=0.02,QFC=0.07,QSC=0.336,QSNC=0.011

 SET VLC=0.0366,VBRC=0.0057,VFC=0.0896,VRC=0.2215,VSC=0.5946

 SET VSNC=0.002

 SET KDET=0.025, KDTE=0., kdbi=0

 set fnight=0.8, per1=1.5, dur1=0.75, per2=3, dur2=0.5

 END $'of proced rat' 

PROCED FMSA1

SET N=1

MOUSE $START $ D AUCV, DM1

SET PB=71.811 $START $ D AUCV, DM1 $MOUSE

SET PFA=1452.38 $START $ D AUCV, DM1 $MOUSE

SET PLA=73.73 $START $ D AUCV, DM1 $MOUSE

SET PRA=61.307 $START $ D AUCV, DM1 $MOUSE

SET PSA=23.23 $START $ D AUCV, DM1 $MOUSE

SET PBRA=56.661 $START $ D AUCV, DM1 $MOUSE

SET PSNA=43.43 $START $ D AUCV, DM1 $MOUSE

SET VMAXC=17.473 $START $ D AUCV, DM1 $MOUSE

SET KM=0.3535 $START $ D AUCV, DM1 $MOUSE

SET BW=0.02525 $START $ D AUCV, DM1 $MOUSE

SET QPC=14.14 $START $ D AUCV, DM1 $MOUSE

SET QCC=14.14 $START $ D AUCV, DM1 $MOUSE

SET QLC=0.16261 $START $ D AUCV, DM1 $MOUSE

SET QBRC=0.03333 $START $ D AUCV, DM1 $MOUSE

SET QFC=0.0707 $START $ D AUCV, DM1 $MOUSE

SET QSC=0.21917 $START $ D AUCV, DM1 $MOUSE

SET QSNC=0.01111 $START $ D AUCV, DM1 $MOUSE

SET VLC=0.055449 $START $ D AUCV, DM1 $MOUSE

SET VBRC=0.016665 $START $ D AUCV, DM1 $MOUSE
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 13

SET VFC=0.0707 $START $ D AUCV, DM1 $MOUSE

SET VRC=0.197758 $START $ D AUCV, DM1 $MOUSE

SET VSC=0.554793 $START $ D AUCV, DM1 $MOUSE

SET VSNC=0.003535 $START $ D AUCV, DM1 $MOUSE

SET KDET=0.02525 $START $ D AUCV, DM1 $MOUSE

SET KDBI=0.092314 $START $ D AUCV, DM1 $MOUSE

END 

PROCED FMSA2

SET N=1

MOUSE $START $ range cv

SET PB=71.811 $START $ range cv $MOUSE

SET PFA=1452.38 $START $ range cv $MOUSE

SET PLA=73.73 $START $ range cv $MOUSE

SET PRA=61.307 $START $ range cv $MOUSE

SET PSA=23.23 $START $ range cv $MOUSE

SET PBRA=56.661 $START $ range cv $MOUSE

SET PSNA=43.43 $START $ range cv $MOUSE

SET VMAXC=17.473 $START $ range cv $MOUSE

SET KM=0.3535 $START $ range cv $MOUSE

SET BW=0.02525 $START $ range cv $MOUSE

SET QPC=14 $START $ range cv $MOUSE

SET QCC=14 $START $ range cv $MOUSE

SET QLC=0.16261 $START $ range cv $MOUSE

SET QBRC=0.03333 $START $ range cv $MOUSE

SET QFC=0.0707 $START $ range cv $MOUSE

SET QSC=0.21917 $START $ range cv $MOUSE

SET QSNC=0.01111 $START $ range cv $MOUSE

SET VLC=0.055449 $START $ range cv $MOUSE

SET VBRC=0.016665 $START $ range cv $MOUSE

SET VFC=0.0707 $START $ range cv $MOUSE

SET VRC=0.197758 $START $ range cv $MOUSE

SET VSC=0.554793 $START $ range cv $MOUSE

SET VSNC=0.003535 $START $ range cv $MOUSE

SET KDET=0.02525 $START $ range cv $MOUSE

SET KDBI=0.092314 $START $ range cv $MOUSE

END 

PROCED FMSA3

SET N=1

MOUSE $START $ D AUCsn, DM1

SET PB=71.811 $START $ D AUCsn, DM1 $MOUSE

SET PFA=1452.38 $START $ D AUCsn, DM1 $MOUSE

SET PLA=73.73 $START $ D aucsn, DM1 $MOUSE

SET PRA=61.307 $START $ D aucsn, DM1 $MOUSE

SET PSA=23.23 $START $ D aucsn, DM1 $MOUSE

SET PBRA=56.661 $START $ D aucsn, DM1 $MOUSE

SET PSNA=43.43 $START $ D aucsn, DM1 $MOUSE

SET VMAXC=17.473 $START $ D aucsn, DM1 $MOUSE

SET KM=0.3535 $START $ D aucsn, DM1 $MOUSE

SET BW=0.02525 $START $ D aucsn, DM1 $MOUSE

SET QPC=14.14 $START $ D aucsn, DM1 $MOUSE

SET QCC=14.14 $START $ D aucsn, DM1 $MOUSE

SET QLC=0.16261 $START $ D aucsn, DM1 $MOUSE

SET QBRC=0.03333 $START $ D aucsn, DM1 $MOUSE

SET QFC=0.0707 $START $ D aucsn, DM1 $MOUSE

SET QSC=0.21917 $START $ D aucsn, DM1 $MOUSE
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 14

SET QSNC=0.01111 $START $ D aucsn, DM1 $MOUSE

SET VLC=0.055449 $START $ D aucsn, DM1 $MOUSE

SET VBRC=0.016665 $START $ D aucsn, DM1 $MOUSE

SET VFC=0.0707 $START $ D aucsn, DM1 $MOUSE

SET VRC=0.197758 $START $ D aucsn, DM1 $MOUSE

SET VSC=0.554793 $START $ D aucsn, DM1 $MOUSE

SET VSNC=0.003535 $START $ D aucsn, DM1 $MOUSE

SET KDET=0.02525 $START $ D aucsn, DM1 $MOUSE

SET KDBI=0.092314 $START $ D aucsn, DM1 $MOUSE

END 

proced FEMmusSA

set hvdprn=.f., tstop=168, points=30000

bolus

set dose= 390, ka=0.20

fmsa1

SET dose=393.9 $START $ D AUCV, DM1 $set dose=390

SET ka=0.202 $START $ D AUCV, DM1 $set ka=0.2

$START $ D AUCV, DM1

fmsa2

SET dose=393.9 $START $ range cv $set dose=390

SET ka=0.202 $START $ range cv $set ka=0.2

$START $ range cv

set dose= 10, ka=2.5, tstop=23.5

fmsa1

SET dose=10.1 $START $ D AUCV, DM1 $set dose=10

SET ka=2.525 $START $ D AUCV, DM1 $set ka=2.5

$START $ D AUCV, DM1

fmsa2

SET dose=10.1 $START $ range cv $set dose=10

SET ka=2.525 $START $ range cv $set ka=2.5

$START $ range cv

END

PROCED MMSA1

SET N=1

MMOUSE $START $ D AUCV, DM1

SET PB=71.811 $START $ D AUCV, DM1 $MMOUSE

SET PFA=1452.38 $START $ D AUCV, DM1 $MMOUSE

SET PLA=73.73 $START $ D AUCV, DM1 $MMOUSE

SET PRA=61.307 $START $ D AUCV, DM1 $MMOUSE

SET PSA=23.23 $START $ D AUCV, DM1 $MMOUSE

SET PBRA=56.661 $START $ D AUCV, DM1 $MMOUSE

SET PSNA=43.43 $START $ D AUCV, DM1 $MMOUSE

SET VMAXC=17.473 $START $ D AUCV, DM1 $MMOUSE

SET KM=0.3535 $START $ D AUCV, DM1 $MMOUSE

SET BW=0.02525 $START $ D AUCV, DM1 $MMOUSE

SET QPC=14.14 $START $ D AUCV, DM1 $MMOUSE

SET QCC=14.14 $START $ D AUCV, DM1 $MMOUSE

SET QLC=0.16261 $START $ D AUCV, DM1 $MMOUSE

SET QBRC=0.03333 $START $ D AUCV, DM1 $MMOUSE

SET QFC=0.0707 $START $ D AUCV, DM1 $MMOUSE

SET QSC=0.21917 $START $ D AUCV, DM1 $MMOUSE

SET QSNC=0.01111 $START $ D AUCV, DM1 $MMOUSE

SET VLC=0.055449 $START $ D AUCV, DM1 $MMOUSE

SET VBRC=0.016665 $START $ D AUCV, DM1 $MMOUSE
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 15

SET VFC=0.0707 $START $ D AUCV, DM1 $MMOUSE

SET VRC=0.197758 $START $ D AUCV, DM1 $MMOUSE

SET VSC=0.554793 $START $ D AUCV, DM1 $MMOUSE

SET VSNC=0.003535 $START $ D AUCV, DM1 $MMOUSE

SET KDET=0.02525 $START $ D AUCV, DM1 $MMOUSE

END 

PROCED MMSA2

SET N=1

MMOUSE $START $ range cv

SET PB=71.811 $START $ range cv $MMOUSE

SET PFA=1452.38 $START $ range cv $MMOUSE

SET PLA=73.73 $START $ range cv $MMOUSE

SET PRA=61.307 $START $ range cv $MMOUSE

SET PSA=23.23 $START $ range cv $MMOUSE

SET PBRA=56.661 $START $ range cv $MMOUSE

SET PSNA=43.43 $START $ range cv $MMOUSE

SET VMAXC=17.473 $START $ range cv $MMOUSE

SET KM=0.3535 $START $ range cv $MMOUSE

SET BW=0.02525 $START $ range cv $MMOUSE

SET QPC=14.14 $START $ range cv $MMOUSE

SET QCC=14.14 $START $ range cv $MMOUSE

SET QLC=0.16261 $START $ range cv $MMOUSE

SET QBRC=0.03333 $START $ range cv $MMOUSE

SET QFC=0.0707 $START $ range cv $MMOUSE

SET QSC=0.21917 $START $ range cv $MMOUSE

SET QSNC=0.01111 $START $ range cv $MMOUSE

SET VLC=0.055449 $START $ range cv $MMOUSE

SET VBRC=0.016665 $START $ range cv $MMOUSE

SET VFC=0.0707 $START $ range cv $MMOUSE

SET VRC=0.197758 $START $ range cv $MMOUSE

SET VSC=0.554793 $START $ range cv $MMOUSE

SET VSNC=0.003535 $START $ range cv $MMOUSE

SET KDET=0.02525 $START $ range cv $MMOUSE

END 

proced MALEmusSA

bolus

set hvdprn=.f., tstop=168, points=30000

set dose= 390, ka=0.2

Mmsa1

SET dose=393.9 $START $ D AUCV, DM1 $set dose=390

SET ka=0.202 $START $ D AUCV, DM1 $set ka=0.2

$START $ D AUCV, DM1

Mmsa2

SET dose=393.9 $START $ range cv $set dose=390

SET ka=0.202 $START $ range cv $set ka=0.2

$START $ range cv

set dose= 10, ka=2.5, tstop=23.5

Mmsa1

SET dose=10.1 $START $ D AUCV, DM1 $set dose=10

SET ka=2.525 $START $ D AUCV, DM1 $set ka=2.5

$START $ D AUCV, DM1

Mmsa2

SET dose=10.1 $START $ range cv $set dose=10

SET ka=2.525 $START $ range cv $set ka=2.5

$START $ range cv
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

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END

proced cancerSA

bolus

set hvdprn=.f., tstop=168, points=30000

set dose= 195, ka=0.2

fmsa1

SET dose=196.95 $START $ D AUCV, DM1 $set dose=195

SET ka=0.202 $START $ D AUCV, DM1 $set ka=0.2

$START $ D AUCV, DM1

END

PROCED RSA1

SET N=1

RAT $START $ D AUCV, DM1

SET PB=58.58 $START $ D AUCV, DM1 $RAT

SET PFA=1452.38 $START $ D AUCV, DM1 $RAT

SET PLA=73.73 $START $ D AUCV, DM1 $RAT

SET PRA=61.307 $START $ D AUCV, DM1 $RAT

SET PSA=23.23 $START $ D AUCV, DM1 $RAT

SET PBRA=56.661 $START $ D AUCV, DM1 $RAT

SET PSNA=43.43 $START $ D AUCV, DM1 $RAT

SET VMAXC=10.302 $START $ D AUCV, DM1 $RAT

SET KM=0.5454 $START $ D AUCV, DM1 $RAT

SET BW=0.2525 $START $ D AUCV, DM1 $RAT

SET QPC=13.13 $START $ D AUCV, DM1 $RAT

SET QCC=13.13 $START $ D AUCV, DM1 $RAT

SET QLC=0.18483 $START $ D AUCV, DM1 $RAT

SET QBRC=0.0202 $START $ D AUCV, DM1 $RAT

SET QFC=0.0707 $START $ D AUCV, DM1 $RAT

SET QSC=0.33936 $START $ D AUCV, DM1 $RAT

SET QSNC=0.01111 $START $ D AUCV, DM1 $RAT

SET VLC=0.036966 $START $ D AUCV, DM1 $RAT

SET VBRC=0.005757 $START $ D AUCV, DM1 $RAT

SET VFC=0.090496 $START $ D AUCV, DM1 $RAT

SET VRC=0.223715 $START $ D AUCV, DM1 $RAT

SET VSC=0.600546 $START $ D AUCV, DM1 $RAT

SET VSNC=0.00202 $START $ D AUCV, DM1 $RAT

SET KDET=0.02525 $START $ D AUCV, DM1 $RAT

END 

PROCED RSA2

SET N=1

RAT $START $ range cv

SET PB=58.58 $START $ range cv $RAT

SET PFA=1452.38 $START $ range cv $RAT

SET PLA=73.73 $START $ range cv $RAT

SET PRA=61.307 $START $ range cv $RAT

SET PSA=23.23 $START $ range cv $RAT

SET PBRA=56.661 $START $ range cv $RAT

SET PSNA=43.43 $START $ range cv $RAT

SET VMAXC=10.302 $START $ range cv $RAT

SET KM=0.5454 $START $ range cv $RAT

SET BW=0.2525 $START $ range cv $RAT

SET QPC=13.13 $START $ range cv $RAT

SET QCC=13.13 $START $ range cv $RAT

SET QLC=0.18483 $START $ range cv $RAT
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 17

SET QBRC=0.0202 $START $ range cv $RAT

SET QFC=0.0707 $START $ range cv $RAT

SET QSC=0.33936 $START $ range cv $RAT

SET QSNC=0.01111 $START $ range cv $RAT

SET VLC=0.036966 $START $ range cv $RAT

SET VBRC=0.005757 $START $ range cv $RAT

SET VFC=0.090496 $START $ range cv $RAT

SET VRC=0.223715 $START $ range cv $RAT

SET VSC=0.600546 $START $ range cv $RAT

SET VSNC=0.00202 $START $ range cv $RAT

SET KDET=0.02525 $START $ range cv $RAT

END 

proced RATSA

set hvdprn=.f., tstop=168, points=30000

bolus

set dose= 92, ka=0.45

Rsa1

SET dose=92.92 $START $ D AUCV, DM1 $set dose=92

SET ka=0.4545 $START $ D AUCV, DM1 $set ka=0.45

$START $ D AUCV, DM1

Rsa2

SET dose=92.92 $START $ range cv $set dose=92

SET ka=0.4545 $START $ range cv $set ka=0.45

$START $ range cv

set dose= 1.7, ka=1.3, tstop=23.5

Rsa1

SET dose=1.717 $START $ D AUCV, DM1 $set dose=1.7

SET ka=1.313 $START $ D AUCV, DM1 $set ka=1.3

$START $ D AUCV, DM1

Rsa2

SET dose=1.717 $START $ range cv $set dose=1.7

SET ka=1.313 $START $ range cv $set ka=1.3

$START $ range cv

END

PROCED ROIL

 CCL2CCL

 RAT

 bolus

 SET N=1, DOSE=94.2, BW=0.147, KA=0.45, TSTOP=8.02

END

DATA ROILDATA (T, CV)

 0.52 12.13

 1.01 8.45

 2.01 4.04

 8.02 0.16

END

PROCED RWAT

 CCL2CCL

 RAT

 bolus

 SET N=1, DOSE=1.66, BW=0.152, KA=1.3, TSTOP=1
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 18

END

DATA RWATDATA (T, CV)

 0.11 0.047

 0.25 0.026

 0.51 0.024

 1.00 0.024

END

PROCED MOIL

 CCL2CCL

 MOUSE

 bolus

 SET N=1, DOSE=365, BW=0.0194, KA=0.20, TSTOP=168.0

END

DATA MOIL1DAT (T, CV)

 0.52 11.1

 0.98 7.8

 2.0 4.0

 8.0 0.21

END

PROCED MWAT

 CCL2CCL

 MOUSE

 bolus

 SET N=1, DOSE=9.7, BW=0.0194, KA=2.5, TSTOP=1

END

DATA MWATDATA (T, CV)

 0.11 0.19

 0.25 0.045

 0.51 0.049

 1.0 0.026

END

PROCED MGAVEXH

 CCL2CCL

 MOUSE

 SET N=5, DOSE=26.6, BW=0.0228, KA=0.2, TSTOP=2

 SET FLOW=10.7, VCHC=2.2

END

PROCED SHOWIT

 DISPLY QPC,QCC,QFC,QLC,QRC,QSC, ...

 VFC,VLC,VRC,VSC, ...

 PFA,PLA,PRA,PSA,PB, ...

 VMAXC,KM,BW,MW,ka,ksi,kai, ...

 VCHC,FLOW,DOSE,IALG,TSTOP,POINTS,contdose,N

END $'of proced showit'

 

proced contmet

set contdose= 2 $start $d contdose, aucv, dm1

set contdose= 4 $start $d contdose, aucv, dm1

set contdose= 10 $start $d contdose, aucv, dm1

set contdose= 30 $start $d contdose, aucv, dm1
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 19

set contdose= 50 $start $d contdose, aucv, dm1

set contdose= 80 $start $d contdose, aucv, dm1

set contdose= 100 $start $d contdose, aucv, dm1

set contdose= 120 $start $d contdose, aucv, dm1

set contdose= 190 $start $d contdose, aucv, dm1

set contdose= 240 $start $d contdose, aucv, dm1

set contdose= 290 $start $d contdose, aucv, dm1

set contdose= 340 $start $d contdose, aucv, dm1

set contdose= 390 $start $d contdose, aucv, dm1

set contdose= 2 $start $range cv

set contdose= 4 $start $range cv

set contdose= 10 $start $range cv

set contdose= 30 $start $range cv

set contdose= 50 $start $range cv

set contdose= 80 $start $range cv

set contdose= 100 $start $range cv

set contdose= 120 $start $range cv

set contdose= 190 $start $range cv

set contdose= 240 $start $range cv

set contdose= 290 $start $range cv

set contdose= 340 $start $range cv

set contdose= 390 $start $range cv

end

proced contoral

CCL2CCL

SET tdur=12,TSTOP=168

set n=0, ka=2.5, dose=0

mouse

contmet

mmouse

contmet

end

proced gavmet

set dose= 2 $start $d dose, aucv, dm1

set dose= 4 $start $d dose, aucv, dm1

set dose= 10 $start $d dose, aucv, dm1

set dose= 30 $start $d dose, aucv, dm1

set dose= 50 $start $d dose, aucv, dm1

set dose= 80 $start $d dose, aucv, dm1

set dose= 100 $start $d dose, aucv, dm1

set dose= 120 $start $d dose, aucv, dm1

set dose= 190 $start $d dose, aucv, dm1

set dose= 240 $start $d dose, aucv, dm1

set dose= 290 $start $d dose, aucv, dm1

set dose= 340 $start $d dose, aucv, dm1

set dose= 390 $start $d dose, aucv, dm1

set dose= 2 $start $range cv

set dose= 4 $start $range cv

set dose= 10 $start $range cv

set dose= 30 $start $range cv

set dose= 50 $start $range cv

set dose= 80 $start $range cv
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 20

set dose= 100 $start $range cv

set dose= 120 $start $range cv

set dose= 190 $start $range cv

set dose= 240 $start $range cv

set dose= 290 $start $range cv

set dose= 340 $start $range cv

set dose= 390 $start $range cv

end

PROCED PERORAL

CCL2CCL

PERDWR

set TSTOP=168

set n=0, ka=2.5, contdose=0

mouse

gavmet

mmouse

gavmet

end

proced testdw

set hvdprn=.f.

CCL2CCL

set TSTOP=168

set n=0, ka=2.5, contdose=0, dose=0

mouse

set dwdose=390 $start $d aucv, dm1

end

proced OIL

set hvdprn=.f.

CCL2CCL

bolus

set TSTOP=168

set n=0, ka=0.2, contdose=0

mouse

gavmet

mmouse

gavmet

end

proced cancer

set hvdprn=.f.

CCL2CCL

bolus

set TSTOP=168

set n=0, ka=0.2, contdose=0

mouse

set dose= 150 $start $d dose $range cl, aucl, cv, aucv, dm1

set dose= 200 $start $d dose $range cl, aucl, cv, aucv, dm1

set dose= 300 $start $d dose $range cl, aucl, cv, aucv, dm1

set dose= 400 $start $d dose $range cl, aucl, cv, aucv, dm1

mmouse

set dose= 150 $start $d dose $range cl, aucl, cv, aucv, dm1

set dose= 200 $start $d dose $range cl, aucl, cv, aucv, dm1

set dose= 300 $start $d dose $range cl, aucl, cv, aucv, dm1
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 21

set dose= 400 $start $d dose $range cl, aucl, cv, aucv, dm1

rat

set dose= 70 $start $d dose $range cl, aucl, cv, aucv, dm1

set dose= 100 $start $d dose $range cl, aucl, cv, aucv, dm1

end

proced gavmet2

set dose= 2 $start $d aucl

set dose= 4 $start $d aucl

set dose= 10 $start $d aucl

set dose= 30 $start $d aucl

set dose= 50 $start $d aucl

set dose= 80 $start $d aucl

set dose= 100 $start $d aucl

set dose= 120 $start $d aucl

set dose= 190 $start $d aucl

set dose= 240 $start $d aucl

set dose= 290 $start $d aucl

set dose= 340 $start $d aucl

set dose= 390 $start $d aucl

set dose= 2 $start $range cl

set dose= 4 $start $range cl

set dose= 10 $start $range cl

set dose= 30 $start $range cl

set dose= 50 $start $range cl

set dose= 80 $start $range cl

set dose= 100 $start $range cl

set dose= 120 $start $range cl

set dose= 190 $start $range cl

set dose= 240 $start $range cl

set dose= 290 $start $range cl

set dose= 340 $start $range cl

set dose= 390 $start $range cl

end

proced OIL2

set hvdprn=.f.

CCL2CCL

bolus

set TSTOP=168

set n=0, ka=0.2, contdose=0

mouse

gavmet2

mmouse

gavmet2

end

proced immuno

set hvdprn=.f.

CCL2CCL

set TSTOP=144

set n=0, ka=2.5, contdose=0, points=24000

mouse

set per1=0.5715

set dwdose= 3.9, bw=0.0303, vsnc=0.0060 $start 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 22

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 44, bw=0.0295, vsnc=0.0051 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 384,bw=0.0300, vsnc=0.0050 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set tstop=168

set per1=0.5715

set dwdose= 3.9, bw=0.0303, vsnc=0.0060 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 44, bw=0.0295, vsnc=0.0051 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 384,bw=0.0300, vsnc=0.0050 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

mmouse

set tstop=168

set per1=0.5715

set dwdose= 4.4, bw=0.0396, vsnc=0.0051 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 46, bw=0.0358, vsnc=0.0050 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 305,bw=0.0351, vsnc=0.0037 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

end

proced immuno2

set hvdprn=.f.

CCL2CCL

set TSTOP=144

set n=0, ka=2.5, contdose=0, points=24000

mouse

set per1=0.5715

set dwdose= 50, bw=0.0295, vsnc=0.0051 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 100 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 150 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 200 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 250 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 300 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 350 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set tstop=168

set dwdose= 50, bw=0.0295, vsnc=0.0051 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 100 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 150 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 200 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 250 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 23

set dwdose= 300 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 350 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

mmouse

set tstop=168

set per1=0.5715

set dwdose= 50, bw=0.0358, vsnc=0.0050 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 100 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 150 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 200 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 250 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

set dwdose= 300 $start 

$d dwdose $range csn, aucsn, cv, aucv, dm1

end

proced immunSA

set hvdprn=.f., tstop=168, points=30000

set dwdose= 3.9, ka=2.5

fmsa3

SET dwdose=3.939 $START $ D AUCsn, DM1 $set dwdose=3.9

SET ka=2.525 $START $ D AUCsn, DM1 $set ka=2.5

$START $ D AUCsn, DM1

set tstop=144

fmsa3

SET dwdose=3.939 $START $ D AUCsn, DM1 $set dwdose=3.9

SET ka=2.525 $START $ D AUCsn, DM1 $set ka=2.5

$START $ D AUCsn, DM1

END

proced acuteneuro

roil

set bw=0.168

set dose=55 $start

$ d dose $range cbr cv aucbr aucv dm1

set dose=95 $start

$ d dose $range cbr cv aucbr aucv dm1

set dose=200 $start

$ d dose $range cbr cv aucbr aucv dm1

set bw=0.226

set dose=55 $start 

$ d dose $range cbr cv aucbr aucv dm1

set dose=95 $start

$ d dose $range cbr cv aucbr aucv dm1

set dose=200 $start

$ d dose $range cbr cv aucbr aucv dm1

end

PROCED neurosa

set hvdprn=.f.

SET N=1
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 24

roil

set bw=0.168, dose=95

$START $ range cbr

SET PB=58.58 $START $ range cbr $RAT $set bw=0.168

SET PFA=1452.38 $START $ range cbr $RAT $set bw=0.168

SET PLA=73.73 $START $ range cbr $RAT $set bw=0.168

SET PRA=61.307 $START $ range cbr $RAT $set bw=0.168

SET PSA=23.23 $START $ range cbr $RAT $set bw=0.168

SET PBRA=56.661 $START $ range cbr $RAT $set bw=0.168

SET PSNA=43.43 $START $ range cbr $RAT $set bw=0.168

SET VMAXC=10.302 $START $ range cbr $RAT $set bw=0.168

SET KM=0.5454 $START $ range cbr $RAT $set bw=0.168

SET BW=0.16968 $START $ range cbr $RAT $set bw=0.168

SET QPC=13.13 $START $ range cbr $RAT $set bw=0.168

SET QCC=13.13 $START $ range cbr $RAT $set bw=0.168

SET QLC=0.18483 $START $ range cbr $RAT $set bw=0.168

SET QBRC=0.0202 $START $ range cbr $RAT $set bw=0.168

SET QFC=0.0707 $START $ range cbr $RAT $set bw=0.168

SET QSC=0.33936 $START $ range cbr $RAT $set bw=0.168

SET QSNC=0.01111 $START $ range cbr $RAT $set bw=0.168

SET VLC=0.036966 $START $ range cbr $RAT $set bw=0.168

SET VBRC=0.005757 $START $ range cbr $RAT $set bw=0.168

SET VFC=0.090496 $START $ range cbr $RAT $set bw=0.168

SET VRC=0.223715 $START $ range cbr $RAT $set bw=0.168

SET VSC=0.600546 $START $ range cbr $RAT $set bw=0.168

SET VSNC=0.00202 $START $ range cbr $RAT $set bw=0.168

SET KDET=0.02525 $START $ range cbr $RAT $set bw=0.168

SET dose=95.95 $START $ range cbr $set dose=95

SET ka=0.4545 $START $ range cbr $set ka=0.45

$START $ range cbr

END 

SET WESITG=.F., GRDCPL=.F., XINCPL=6.0, YINCPL=4.0

SET DEVPLT=1,CJVITG=.F.,HVDPRN=.T.
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 25

GISIR3.CSL

PROGRAM: GIsir.CSL

 'Modified to describe off-gasing so we can refine gavage parms'

 'Has provision for two/one compartment stomach comparisons. '

 'M.L. Gargas '

 'Revised 4/16/2001 and 8/31/01 by LM Sweeney' 

 'revised 12/17/2001, add suicide inhib rel. to tot enz'

 'revised 6/25/2002 revise drinking water scenario'

INITIAL 

1.. FORMAT(/,' GI.CSL, Rev. 1/19/90 at 9:00 am ',/)

 WRITE(0,1) $ WRITE(7,1)

 CONSTANT BW = 0.029 $'Body weight (kg) for MICE'

 CONSTANT QPC = 15. $'Alveolar ventilation rate (l/hr)'

 CONSTANT QCC = 15. $'Cardiac output (l/hr)'

'Flows to Tissue Compartments'

 CONSTANT QLC = 0.24 $'Fractional blood flow to liver'

 CONSTANT QFC = 0.02 $'Fractional blood flow to fat'

 CONSTANT QSC = 0.18 $'Fractional blood flow to slow'

 CONSTANT QSNC = 0.011 $'Fractional blood flow to spleen'

 CONSTANT QBRC = 0.02 $'Fractional blood flow to brain'

 QRC = 1.0 - (QFC + QSC + QLC + QBRC + QSNC)

'Volumes of Tissue Compartments'

 CONSTANT VLC = 0.04 $'Fraction liver tissue'

 CONSTANT VFC = 0.04 $'Fraction fat tissue'

 CONSTANT VRC = 0.05 $'Fraction Rapidly Perf tissue'

 CONSTANT VBRC = 0.0057 $'Fraction of brain'

 CONSTANT VSC = 0.5946 $'Fraction spt'

 CONSTANT VSNC = 0.0035 $'Fraction spleen'

'Partition Coefficients' 

 CONSTANT PLA = 8.60 $'Liver/air partition coefficient'

 CONSTANT PFA = 263.0 $'Fat/air partition coefficient'

 CONSTANT PSA = 3.15 $'Muscle/air (Slow Perf) partition'

 CONSTANT PSNA = 53 $'spleen/air partition'

 CONSTANT PRA = 8.60 $'Richly perfused tissue/air partition'

 CONSTANT PBRA = 8.60 $'brain/air partition'

 CONSTANT PB = 10.8 $'Blood/air partition coefficient'

'Other Compound Specific Parameters'

 CONSTANT MW = 133.5 $'Molecular weight (g/mol)'

 CONSTANT VMAXC = 0.419 $'Maximum Velocity of Metabol.'

 CONSTANT VMAXRC = 0.419 $'Maximum Velocity of Metabol. in rpt'

 CONSTANT KM = 5.75 $'Michaelis Menten Constant'

 CONSTANT KFC = 0.0 $'First order rate constant'

 CONSTANT DOSE = 0.0 $'BOLUS GAVAGE dose (mg/kg/day)'

 CONSTANT ka = 0.6 $'Stomach Absorption Rate constant'

 CONSTANT kai = 0.0 $'Intestine Absorption Rate constant'

 CONSTANT ksi = 0.0 $'Stomach/Intestine Xfer Rate Constant'

'Timing commands'

 CONSTANT TSTOP = 6. $'Length of experiment (hrs)'

 CONSTANT POINTS = 72. $'Number of points in plot'

 CINT = TSTOP/POINTS
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 26

 constant contdose=0 $'continuous oral dose (mg/kg/d)'

 Constant tdur =24 $'duration of continuous ingestion (hr)'

 CONSTANT TCHNG=120 $'allows exposure free weekends (hr)'

 array drtime(6) $'splits DW bolus into 6 boluses'

 array drpct(6) $'pct of dw ingestion at each bolus'

 constant drtime=6*0.0, drpct=6*0.0

 constant dwdose=0 $'daily dose for drinking water mg/kg/d'

 constant per1 = 1.5 $'period during dark (hr)'

 constant dur1 = 0.75 $'duration of drinking during dark (hr)'

 constant per2=3 $'period during light (hr)'

 constant dur2=0.5 $'duration of drinking during light (hr)'

 constant Fnight=0.8 $'fraction of drinking during night'

'Constants associated with Off-Gasing Chamber'

 CONSTANT VCHC = 2.54 $'Volume of Chamber (liters)'

 CONSTANT FLOW = 7.2 $'Flow thru Chamber (liters/hr)'

 CONSTANT N = 1 $'Number of animals in chamber'

'Scaled parameters calculated in this section of Program'

 QC=QCC*BW**0.7 $ QP=QPC*BW**0.7

QL=QLC*QC $ QF=QFC*QC $ QS=QSC*QC $ QR=QRC*QC $QBR=QBRC*QC $QSN=QSNC*QC

VL=VLC*BW $ VF=VFC*BW $ VS=VSC*BW $ VR=VRC*BW $ VBR=VBRC*BW $VSN=VSNC*BW

PL=PLA/PB $ PR=PRA/PB $ PS=PSA/PB $ PF=PFA/PB $pbr=pbra/pb $PSN=PSNA/PB

NEWDAY=0

INTEGER I

I=1

 VMAX = VMAXC*BW**0.7 $ DOSE2=0 $ KF=KFC/BW**0.3

 VMAXR =VMAXRC*BW**0.7

 VCH = VCHC-BW*N

 IF(VCH .LE. 0.0) WRITE(0,2)

2.. FORMAT(//,'Chamber Volume Less than ZERO!!!',//)

'parameters associated with suicide inact of enz and resynthesis'

CONSTANT Kdes=0 $'rate of enzyme activity loss thru inhibition by ES mech'

Constant kdte=0 $'rate of enzyme activity loss thru inhibition by TE mech'

Constant kdfe=0 $'rate of enzyme activity loss thru inhibition by FE mech'

Constant kdbi=0 $'rate of enzyme activity loss thru inhibition by BI mech'

 CONSTANT Kdet=0.025 $'normal turnover of enzyme'

END $'End of initial' 

DYNAMIC 

 ALGORITHM IALG = 2 $'Gear method for stiff systems'

 TERMT(T.GE.TSTOP) 

 CR = AR/VR $ CS = AS/VS $ CF = AF/VF $ CL = AL/VL $ CBR = ABR/VBR

 CSN = ASN/VSN

 BODY = AL + AR + AS + AF + ABR + ASN + STOM + INT

 BURDEN = AM + BODY

 

DERIVATIVE

 

 'ACH = Amount in Off Gasing Chamber (mg)'

 RACH = N*QP*(CX - CI) - CI*FLOW

 ACH = INTEG(RACH, 0)
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 27

 CI = ACH/VCH

 RLOST = CI*FLOW

 LOST = INTEG(RLOST, 0.0)

 PPMOUT = CI*24450./MW

PROCEDURAL

 IF( T .LT. (drtime(I) + NEWDAY) ) GO TO SKIP2

 DOSE2 = dose2 + dose*bw*drpct(I)*PULSE(0.0,168.0,tchng)

 I = I + 1

 IF(I .LT. 7 ) GO TO SKIP2

 I = I - 6

 NEWDAY = NEWDAY + 24.0

SKIP2.. CONTINUE

END $'of PROCEDURAL'

 'Mass Balance for the Stomach'

 DWing = (dwdose/24)*bw*2*(PULSE(0.0,PER1,DUR1)*Fnight*per1/dur1* ...

PULSE(0., 24., 12.)+ PULSE(0.0,PER2,DUR2)*(1-Fnight)*per2/dur2* ...

(1-PULSE(0., 24., 12.)))

 RSTOM = -ka*STOM -ksi*STOM +contdose*bw/tdur*PULSE(0.0,24.0,TDUR) ...

 + DWing

 STOM = INTEG(RSTOM, 0)+dose2

 'Mass Balance for the Intestine'

 RINT = +ksi*STOM -kai*INT

 INT = INTEG(RINT, 0.0)

 'CA = Concentration in arterial blood (mg/l)'

 CA = (QC*CV+QP*CI)/(QC+(QP/PB))

 AUCB = INTEG(CA,0.)

 CX = CA/PB 

 'AS = Amount in slowly perfused tissues (mg)'

 RAS = QS*(CA-CVS)

 AS = INTEG(RAS,0.)

 CVS = AS/(VS*PS)

 'ASN = Amount in spleen (mg)'

 RASN = QSN*(CA-CVSN)

 ASN = INTEG(RASN,0.)

 CSN = ASN/VSN

 CVSN = CSN/PSN

 aucsn= integ(CSN,0.)

 

 'AR = Amount in rapidly perfused tissues (mg)' 

 RAR = QR*(CA-CVR) - RAMR

 AR = INTEG(RAR,0.)

 CVR = AR/(VR*PR)

 'ABR = Amount in rapidly perfused tissues (mg)' 

 RABR = QBR*(CA-CVBR) 

 ABR = INTEG(RABR,0.)

 CBR = ABR/VBR

 CVBR = ABR/(VBR*PBR)

 aucbr = integ(cbr, 0.)

 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 28

 'AF = Amount in fat tissue (mg)'

 RAF = QF*(CA-CVF) 

 AF = INTEG(RAF,0.)

 CVF = AF/(VF*PF)

 

 'VMT = maximal rate of metabolism'

 RVMT = (VMAX-VMT)*KDET-KDES*RAML*RAML-KDTE*RAML*VMT ...

 -KDFE*RAML*VMT*KM/(KM+ CVL)-KDBI*RAML

 VMT = INTEG(RVMT, VMAX)

 'AM = Amount metabolized (mg)' 

 RAML = (VMT*CVL)/(KM+CVL) + KF*CVL*VL 

 RAMR = (VMAXR*CVR)/(KM+CVR) 

 RAM = RAML + RAMR

 AM = INTEG(RAM, 0.)

 AML = INTEG(RAML,0)

 'AL = Amount in liver tissue (mg)'

 RAL = QL*(CA-CVL) - RAML + ka*STOM + kai*INT

 AL = INTEG(RAL,0.)

 CL = AL/VL

 AUCL = INTEG(CL,0.)

 CVL = AL/(VL*PL)

 

 DM1 = AML/VL

 DM = DM1*1000/MW

 'CV = Mixed venous blood concentration (mg/l)' 

 CV = (QF*CVF + QL*CVL + QS*CVS + QR*CVR + QBR*CVBR +QSN*CVSN)/QC

 aucv= integ(cv, 0.) 

 

END $'End of derivative'

END $'End of dynamic' 

END $'End of program' 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 29

EXHSIR.CMD

SET TITLE = 'EXHALED BREATH MODEL'

PREPAR T,CCH,CV,PPMOUT, AUCV, DM1, csn

SET TJNITG = 1.0 $'Threshold for Jacobian Error Messages'

SET TSMITG = .T. $'Two sided matrix evaluation for increased accur.'

SET WESItG=.F.

SET NSTP = 1000 $'Allow the integrator to take very small steps'

PROCED CCL2CCL $'1,1,2-TRICHLOROETHANE'

SET TCHNG=6.,TSTOP=8.,N=5

SET MW=133.41

SET FCH=10.8,vmch=2.2,POINTS=2400,PLT=6

SET KFC=0.0,ABG0=0.0,KBG=0.0

END

proced minh1000

mouse

ccl2ccl

set conc=985.2, tchng=6, tstop=15, N=5

set bw=0.0194

end

proced minh500

mouse

ccl2ccl

set conc=492.6, TCHNG=4, N=5

set bw=0.0205

end

proced minh250

mouse

ccl2ccl

set conc=248.3, tchng=6, tstop=11, N=5

set bw=0.0196

end

PROCED M100

 CCL2CCL

 MOUSE

 SET CONC=100, N=0, BW=0.0228, VMCH=2200, FCH=10800

 SET TEXPOS=6, TCHNG=170, TSTOP=168

END

DATA M100 (T, CV)

 4.07 0.608

 6.1 0.951

 6.3 0.960

 8 0.022

52.07 1.84

54.07 1.73

54.3 0.43

56 0.007

100.07 1.98
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 30

102.07 2.16

102.3 0.592

104 0.055

END

PROCED rat $'revised by LMS 5/1/01, 041702, 071803'

'note addition of brain, spleen, and Vmaxrc'

'values from brown et al., 1997' 

SET TITLE = ' 1,1,2-TCE RAT' 

 SET VMAXC=10.2,VMAXRC=0,KM=0.54,KFC=0.0, kdte=0, kdbi=0

 SET BW=0.25,QPC=13,QCC=13

 SET QLC=0.183,QFC=0.07, qbrc=0.02, qsc=0.336,QSNC=0.011 

 SET VLC=0.0366, VFC=0.0896, vbrc=0.0057, vsc=0.5946, VRC=.2215

 SET VSNC=0.002

 SET PB=58.,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1

 SET PSNA=43

 END $'of proced rat' 

PROCED R100

 CCL2CCL

 RAT

 SET CONC=100, N=1, BW=0.160, VMCH=2200, FCH=10800

END

DATA R100DATA (T, CV)

 4.08 1.73

 6.06 1.88

 6.3 0.78

 8.0 0.15

END

PROCED MOUSE $'PHYSIOL FROM BROWN ET AL 1997 last rev 050902'

 SET TITLE = ' 1,1,2-TCE FEMALE MOUSE' 

 SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1

 SET PSNA=43

 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.0

 SET BW=0.025,QPC=14,QCC=14

 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011

 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493

 SET VSNC=0.0035

 SET KDET=0.025, KDbi=0.0914

 END $'of proced mouse' 

PROCED MMOUSE $'PHYSIOL FROM BROWN ET AL 1997 last rev 050902'

 SET TITLE = ' 1,1,2-TCE MALE MOUSE' 

 SET MW=133.41,PB=71.1,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1

 SET PSNA=43

 SET VMAXC=17.3,VMAXRC=0,KM=0.35,KFC=0.0

 SET BW=0.025,QPC=14,QCC=14

 SET QLC=0.161,QBRC=0.033,QFC=0.07,QSC=0.217, QSNC=0.011

 SET VLC=0.0549,VBRC=0.0165,VFC=0.07,VRC=0.1958,VSC=0.5493

 SET VSNC=0.0035

 SET KDET=0.025, KDBI=0.0

 END $'of proced Mmouse' 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 31

PROCED rat 

 SET TITLE = ' 1,1,2-TCE RAT' 

 SET MW=133.41,PB=58.,PFA=1438,PLA=73,PRA=60.7,PSA=23,PBRA=56.1

 SET PSNA=43

 SET VMAXC=10.2,VMAXRC=0,KM=0.54,KFC=0.0

 SET BW=0.25,QPC=13,QCC=13

 SET QLC=0.183,QBRC=0.02,QFC=0.07,QSC=0.336,QSNC=0.011

 SET VLC=0.0366,VBRC=0.0057,VFC=0.0896,VRC=0.2215,VSC=0.5946

 SET VSNC=0.002

 SET KDET=0.025, KDBI=0.

 END $'of proced rat' 

PROCED FMSA1

SET N=0

MOUSE $START $ D AUCV, DM1

SET PB=71.811 $START $ D AUCV, DM1 $MOUSE

SET PFA=1452.38 $START $ D AUCV, DM1 $MOUSE

SET PLA=73.73 $START $ D AUCV, DM1 $MOUSE

SET PRA=61.307 $START $ D AUCV, DM1 $MOUSE

SET PSA=23.23 $START $ D AUCV, DM1 $MOUSE

SET PBRA=56.661 $START $ D AUCV, DM1 $MOUSE

SET PSNA=43.43 $START $ D AUCV, DM1 $MOUSE

SET VMAXC=17.473 $START $ D AUCV, DM1 $MOUSE

SET KM=0.3535 $START $ D AUCV, DM1 $MOUSE

SET BW=0.02525 $START $ D AUCV, DM1 $MOUSE

SET QPC=14.14 $START $ D AUCV, DM1 $MOUSE

SET QCC=14.14 $START $ D AUCV, DM1 $MOUSE

SET QLC=0.16261 $START $ D AUCV, DM1 $MOUSE

SET QBRC=0.03333 $START $ D AUCV, DM1 $MOUSE

SET QFC=0.0707 $START $ D AUCV, DM1 $MOUSE

SET QSC=0.21917 $START $ D AUCV, DM1 $MOUSE

SET QSNC=0.01111 $START $ D AUCV, DM1 $MOUSE

SET VLC=0.055449 $START $ D AUCV, DM1 $MOUSE

SET VBRC=0.016665 $START $ D AUCV, DM1 $MOUSE

SET VFC=0.0707 $START $ D AUCV, DM1 $MOUSE

SET VRC=0.197758 $START $ D AUCV, DM1 $MOUSE

SET VSC=0.554793 $START $ D AUCV, DM1 $MOUSE

SET VSNC=0.003535 $START $ D AUCV, DM1 $MOUSE

SET KDET=0.02525 $START $ D AUCV, DM1 $MOUSE

SET KDBI=0.092314 $START $ D AUCV, DM1 $MOUSE

END 

PROCED FMSA2

SET N=0

MOUSE $START $ range cv

SET PB=71.811 $START $ range cv $MOUSE

SET PFA=1452.38 $START $ range cv $MOUSE

SET PLA=73.73 $START $ range cv $MOUSE

SET PRA=61.307 $START $ range cv $MOUSE

SET PSA=23.23 $START $ range cv $MOUSE

SET PBRA=56.661 $START $ range cv $MOUSE

SET PSNA=43.43 $START $ range cv $MOUSE

SET VMAXC=17.473 $START $ range cv $MOUSE

SET KM=0.3535 $START $ range cv $MOUSE

SET BW=0.02525 $START $ range cv $MOUSE

SET QPC=14.14 $START $ range cv $MOUSE

SET QCC=14.14 $START $ range cv $MOUSE
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 32

SET QLC=0.16261 $START $ range cv $MOUSE

SET QBRC=0.03333 $START $ range cv $MOUSE

SET QFC=0.0707 $START $ range cv $MOUSE

SET QSC=0.21917 $START $ range cv $MOUSE

SET QSNC=0.01111 $START $ range cv $MOUSE

SET VLC=0.055449 $START $ range cv $MOUSE

SET VBRC=0.016665 $START $ range cv $MOUSE

SET VFC=0.0707 $START $ range cv $MOUSE

SET VRC=0.197758 $START $ range cv $MOUSE

SET VSC=0.554793 $START $ range cv $MOUSE

SET VSNC=0.003535 $START $ range cv $MOUSE

SET KDET=0.02525 $START $ range cv $MOUSE

SET KDBI=0.092314 $START $ range cv $MOUSE

END 

PROCED FMSA3

SET N=0

MOUSE $START $ D aucsn, DM1

SET PB=71.811 $START $ D aucsn, DM1 $MOUSE

SET PFA=1452.38 $START $ D aucsn, DM1 $MOUSE

SET PLA=73.73 $START $ D aucsn, DM1 $MOUSE

SET PRA=61.307 $START $ D aucsn, DM1 $MOUSE

SET PSA=23.23 $START $ D aucsn, DM1 $MOUSE

SET PBRA=56.661 $START $ D aucsn, DM1 $MOUSE

SET PSNA=43.43 $START $ D aucsn, DM1 $MOUSE

SET VMAXC=17.473 $START $ D aucsn, DM1 $MOUSE

SET KM=0.3535 $START $ D aucsn, DM1 $MOUSE

SET BW=0.02525 $START $ D aucsn, DM1 $MOUSE

SET QPC=14.14 $START $ D aucsn, DM1 $MOUSE

SET QCC=14.14 $START $ D aucsn, DM1 $MOUSE

SET QLC=0.16261 $START $ D aucsn, DM1 $MOUSE

SET QBRC=0.03333 $START $ D aucsn, DM1 $MOUSE

SET QFC=0.0707 $START $ D aucsn, DM1 $MOUSE

SET QSC=0.21917 $START $ D aucsn, DM1 $MOUSE

SET QSNC=0.01111 $START $ D aucsn, DM1 $MOUSE

SET VLC=0.055449 $START $ D aucsn, DM1 $MOUSE

SET VBRC=0.016665 $START $ D aucsn, DM1 $MOUSE

SET VFC=0.0707 $START $ D aucsn, DM1 $MOUSE

SET VRC=0.197758 $START $ D aucsn, DM1 $MOUSE

SET VSC=0.554793 $START $ D aucsn, DM1 $MOUSE

SET VSNC=0.003535 $START $ D aucsn, DM1 $MOUSE

SET KDET=0.02525 $START $ D aucsn, DM1 $MOUSE

SET KDBI=0.092314 $START $ D aucsn, DM1 $MOUSE

END 

proced FEMmusSA

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=6, TCHNG=170, TSTOP=168

set CONC= 100

fmsa1

SET CONC=101 $START $ D AUCV, DM1 $set CONC=100

$START $ D AUCV, DM1

fmsa2

SET conc=101 $START $ range cv $set CONC=100

$START $ range cv
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 33

END

PROCED MMSA1

SET N=0

MMOUSE $START $ D AUCV, DM1

SET PB=71.811 $START $ D AUCV, DM1 $MMOUSE

SET PFA=1452.38 $START $ D AUCV, DM1 $MMOUSE

SET PLA=73.73 $START $ D AUCV, DM1 $MMOUSE

SET PRA=61.307 $START $ D AUCV, DM1 $MMOUSE

SET PSA=23.23 $START $ D AUCV, DM1 $MMOUSE

SET PBRA=56.661 $START $ D AUCV, DM1 $MMOUSE

SET PSNA=43.43 $START $ D AUCV, DM1 $MMOUSE

SET VMAXC=17.473 $START $ D AUCV, DM1 $MMOUSE

SET KM=0.3535 $START $ D AUCV, DM1 $MMOUSE

SET BW=0.02525 $START $ D AUCV, DM1 $MMOUSE

SET QPC=14.14 $START $ D AUCV, DM1 $MMOUSE

SET QCC=14.14 $START $ D AUCV, DM1 $MMOUSE

SET QLC=0.16261 $START $ D AUCV, DM1 $MMOUSE

SET QBRC=0.03333 $START $ D AUCV, DM1 $MMOUSE

SET QFC=0.0707 $START $ D AUCV, DM1 $MMOUSE

SET QSC=0.21917 $START $ D AUCV, DM1 $MMOUSE

SET QSNC=0.01111 $START $ D AUCV, DM1 $MMOUSE

SET VLC=0.055449 $START $ D AUCV, DM1 $MMOUSE

SET VBRC=0.016665 $START $ D AUCV, DM1 $MMOUSE

SET VFC=0.0707 $START $ D AUCV, DM1 $MMOUSE

SET VRC=0.197758 $START $ D AUCV, DM1 $MMOUSE

SET VSC=0.554793 $START $ D AUCV, DM1 $MMOUSE

SET VSNC=0.003535 $START $ D AUCV, DM1 $MMOUSE

SET KDET=0.02525 $START $ D AUCV, DM1 $MMOUSE

END 

PROCED MMSA2

SET N=0

MMOUSE $START $ range cv

SET PB=71.811 $START $ range cv $MMOUSE

SET PFA=1452.38 $START $ range cv $MMOUSE

SET PLA=73.73 $START $ range cv $MMOUSE

SET PRA=61.307 $START $ range cv $MMOUSE

SET PSA=23.23 $START $ range cv $MMOUSE

SET PBRA=56.661 $START $ range cv $MMOUSE

SET PSNA=43.43 $START $ range cv $MMOUSE

SET VMAXC=17.473 $START $ range cv $MMOUSE

SET KM=0.3535 $START $ range cv $MMOUSE

SET BW=0.02525 $START $ range cv $MMOUSE

SET QPC=14.14 $START $ range cv $MMOUSE

SET QCC=14.14 $START $ range cv $MMOUSE

SET QLC=0.16261 $START $ range cv $MMOUSE

SET QBRC=0.03333 $START $ range cv $MMOUSE

SET QFC=0.0707 $START $ range cv $MMOUSE

SET QSC=0.21917 $START $ range cv $MMOUSE

SET QSNC=0.01111 $START $ range cv $MMOUSE

SET VLC=0.055449 $START $ range cv $MMOUSE

SET VBRC=0.016665 $START $ range cv $MMOUSE

SET VFC=0.0707 $START $ range cv $MMOUSE

SET VRC=0.197758 $START $ range cv $MMOUSE

SET VSC=0.554793 $START $ range cv $MMOUSE
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 34

SET VSNC=0.003535 $START $ range cv $MMOUSE

SET KDET=0.02525 $START $ range cv $MMOUSE

END 

proced MALEmusSA

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=6, TCHNG=170, TSTOP=168

set CONC= 100

Mmsa1

SET CONC=101 $START $ D AUCV, DM1 $set CONC=100

$START $ D AUCV, DM1

Mmsa2

SET CONC=101 $START $ range cv $set CONC=100

$START $ range cv

END

proced cancerSA

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168

set CONC= 27

fmsa1

SET CONC=27.27 $START $ D AUCV, DM1 $set CONC=27

$START $ D AUCV, DM1

END

PROCED RSA1

SET N=0

RAT $START $ D AUCV, DM1

SET PB=58.58 $START $ D AUCV, DM1 $RAT

SET PFA=1452.38 $START $ D AUCV, DM1 $RAT

SET PLA=73.73 $START $ D AUCV, DM1 $RAT

SET PRA=61.307 $START $ D AUCV, DM1 $RAT

SET PSA=23.23 $START $ D AUCV, DM1 $RAT

SET PBRA=56.661 $START $ D AUCV, DM1 $RAT

SET PSNA=43.43 $START $ D AUCV, DM1 $RAT

SET VMAXC=10.302 $START $ D AUCV, DM1 $RAT

SET KM=0.5454 $START $ D AUCV, DM1 $RAT

SET BW=0.2525 $START $ D AUCV, DM1 $RAT

SET QPC=13.13 $START $ D AUCV, DM1 $RAT

SET QCC=13.13 $START $ D AUCV, DM1 $RAT

SET QLC=0.18483 $START $ D AUCV, DM1 $RAT

SET QBRC=0.0202 $START $ D AUCV, DM1 $RAT

SET QFC=0.0707 $START $ D AUCV, DM1 $RAT

SET QSC=0.33936 $START $ D AUCV, DM1 $RAT

SET QSNC=0.01111 $START $ D AUCV, DM1 $RAT

SET VLC=0.036966 $START $ D AUCV, DM1 $RAT

SET VBRC=0.005757 $START $ D AUCV, DM1 $RAT

SET VFC=0.090496 $START $ D AUCV, DM1 $RAT

SET VRC=0.223715 $START $ D AUCV, DM1 $RAT

SET VSC=0.600546 $START $ D AUCV, DM1 $RAT

SET VSNC=0.00202 $START $ D AUCV, DM1 $RAT

SET KDET=0.02525 $START $ D AUCV, DM1 $RAT

END 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 35

PROCED RSA2

SET N=0

RAT $START $ range cv

SET PB=58.58 $START $ range cv $RAT

SET PFA=1452.38 $START $ range cv $RAT

SET PLA=73.73 $START $ range cv $RAT

SET PRA=61.307 $START $ range cv $RAT

SET PSA=23.23 $START $ range cv $RAT

SET PBRA=56.661 $START $ range cv $RAT

SET PSNA=43.43 $START $ range cv $RAT

SET VMAXC=10.302 $START $ range cv $RAT

SET KM=0.5454 $START $ range cv $RAT

SET BW=0.2525 $START $ range cv $RAT

SET QPC=13.13 $START $ range cv $RAT

SET QCC=13.13 $START $ range cv $RAT

SET QLC=0.18483 $START $ range cv $RAT

SET QBRC=0.0202 $START $ range cv $RAT

SET QFC=0.0707 $START $ range cv $RAT

SET QSC=0.33936 $START $ range cv $RAT

SET QSNC=0.01111 $START $ range cv $RAT

SET VLC=0.036966 $START $ range cv $RAT

SET VBRC=0.005757 $START $ range cv $RAT

SET VFC=0.090496 $START $ range cv $RAT

SET VRC=0.223715 $START $ range cv $RAT

SET VSC=0.600546 $START $ range cv $RAT

SET VSNC=0.00202 $START $ range cv $RAT

SET KDET=0.02525 $START $ range cv $RAT

END 

proced RATSA

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=6, TCHNG=170, TSTOP=168

set CONC= 100

Rsa1

SET CONC=101 $START $ D AUCV, DM1 $set CONC=100

$START $ D AUCV, DM1

Rsa2

SET CONC=101 $START $ range cv $set CONC=100

$START $ range cv

END

proced inhmet

set conc= 0.015 $start $d conc, aucv, dm1

set conc= 0.02 $start $d conc, aucv, dm1

set conc= 0.025 $start $d conc, aucv, dm1

set conc= 0.03 $start $d conc, aucv, dm1

set conc= 0.035 $start $d conc, aucv, dm1

set conc= 0.04 $start $d conc, aucv, dm1

set conc= 0.045 $start $d conc, aucv, dm1

set conc= 0.05 $start $d conc, aucv, dm1

set conc= 0.055 $start $d conc, aucv, dm1

set conc= 0.06 $start $d conc, aucv, dm1

set conc= 0.065 $start $d conc, aucv, dm1

set conc= 0.07 $start $d conc, aucv, dm1

set conc= 0.075 $start $d conc, aucv, dm1
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 36

set conc= 0.08 $start $d conc, aucv, dm1

set conc= 0.085 $start $d conc, aucv, dm1

set conc= 0.09 $start $d conc, aucv, dm1

set conc= 0.095 $start $d conc, aucv, dm1

set conc= 0.1 $start $d conc, aucv, dm1

set conc= 0.15 $start $d conc, aucv, dm1

set conc= 0.2 $start $d conc, aucv, dm1

set conc= 0.25 $start $d conc, aucv, dm1

set conc= 0.3 $start $d conc, aucv, dm1

set conc= 0.35 $start $d conc, aucv, dm1

set conc= 0.4 $start $d conc, aucv, dm1

set conc= 0.45 $start $d conc, aucv, dm1

set conc= 0.5 $start $d conc, aucv, dm1

set conc= 0.55 $start $d conc, aucv, dm1

set conc= 0.6 $start $d conc, aucv, dm1

set conc= 0.65 $start $d conc, aucv, dm1

set conc= 0.7 $start $d conc, aucv, dm1

set conc= 0.75 $start $d conc, aucv, dm1

set conc= 0.8 $start $d conc, aucv, dm1

set conc= 0.85 $start $d conc, aucv, dm1

set conc= 0.9 $start $d conc, aucv, dm1

set conc= 0.95 $start $d conc, aucv, dm1

set conc= 1 $start $d conc, aucv, dm1

set conc= 1.5 $start $d conc, aucv, dm1

set conc= 2 $start $d conc, aucv, dm1

set conc= 2.5 $start $d conc, aucv, dm1

set conc= 3 $start $d conc, aucv, dm1

set conc= 3.5 $start $d conc, aucv, dm1

set conc= 4 $start $d conc, aucv, dm1

set conc= 4.5 $start $d conc, aucv, dm1

set conc= 5 $start $d conc, aucv, dm1

set conc= 5.5 $start $d conc, aucv, dm1

set conc= 6 $start $d conc, aucv, dm1

set conc= 6.5 $start $d conc, aucv, dm1

set conc= 7 $start $d conc, aucv, dm1

set conc= 7.5 $start $d conc, aucv, dm1

set conc= 8 $start $d conc, aucv, dm1

set conc= 8.5 $start $d conc, aucv, dm1

set conc= 9 $start $d conc, aucv, dm1

set conc= 9.5 $start $d conc, aucv, dm1

set conc= 10 $start $d conc, aucv, dm1

set conc= 15 $start $d conc, aucv, dm1

set conc= 20 $start $d conc, aucv, dm1

set conc= 25 $start $d conc, aucv, dm1

set conc= 30 $start $d conc, aucv, dm1

set conc= 35 $start $d conc, aucv, dm1

set conc= 40 $start $d conc, aucv, dm1

set conc= 45 $start $d conc, aucv, dm1

set conc= 50 $start $d conc, aucv, dm1

set conc= 55 $start $d conc, aucv, dm1

set conc= 60 $start $d conc, aucv, dm1

set conc= 65 $start $d conc, aucv, dm1

set conc= 70 $start $d conc, aucv, dm1

set conc= 75 $start $d conc, aucv, dm1

set conc= 80 $start $d conc, aucv, dm1

set conc= 85 $start $d conc, aucv, dm1

set conc= 90 $start $d conc, aucv, dm1
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 37

set conc= 95 $start $d conc, aucv, dm1

set conc= 100 $start $d conc, aucv, dm1

set conc= 110 $start $d conc, aucv, dm1

set conc= 120 $start $d conc, aucv, dm1

set conc= 130 $start $d conc, aucv, dm1

set conc= 140 $start $d conc, aucv, dm1

set conc= 150 $start $d conc, aucv, dm1

set conc= 160 $start $d conc, aucv, dm1

set conc= 170 $start $d conc, aucv, dm1

set conc= 180 $start $d conc, aucv, dm1

set conc= 190 $start $d conc, aucv, dm1

set conc= 200 $start $d conc, aucv, dm1

set conc= 210 $start $d conc, aucv, dm1

set conc= 220 $start $d conc, aucv, dm1

set conc= 230 $start $d conc, aucv, dm1

set conc= 240 $start $d conc, aucv, dm1

set conc= 250 $start $d conc, aucv, dm1

set conc= 260 $start $d conc, aucv, dm1

set conc= 0.015 $start $range cv

set conc= 0.02 $start $range cv

set conc= 0.025 $start $range cv

set conc= 0.03 $start $range cv

set conc= 0.035 $start $range cv

set conc= 0.04 $start $range cv

set conc= 0.045 $start $range cv

set conc= 0.05 $start $range cv

set conc= 0.055 $start $range cv

set conc= 0.06 $start $range cv

set conc= 0.065 $start $range cv

set conc= 0.07 $start $range cv

set conc= 0.075 $start $range cv

set conc= 0.08 $start $range cv

set conc= 0.085 $start $range cv

set conc= 0.09 $start $range cv

set conc= 0.095 $start $range cv

set conc= 0.1 $start $range cv

set conc= 0.15 $start $range cv

set conc= 0.2 $start $range cv

set conc= 0.25 $start $range cv

set conc= 0.3 $start $range cv

set conc= 0.35 $start $range cv

set conc= 0.4 $start $range cv

set conc= 0.45 $start $range cv

set conc= 0.5 $start $range cv

set conc= 0.55 $start $range cv

set conc= 0.6 $start $range cv

set conc= 0.65 $start $range cv

set conc= 0.7 $start $range cv

set conc= 0.75 $start $range cv

set conc= 0.8 $start $range cv

set conc= 0.85 $start $range cv

set conc= 0.9 $start $range cv

set conc= 0.95 $start $range cv

set conc= 1 $start $range cv

set conc= 1.5 $start $range cv

set conc= 2 $start $range cv
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 38

set conc= 2.5 $start $range cv

set conc= 3 $start $range cv

set conc= 3.5 $start $range cv

set conc= 4 $start $range cv

set conc= 4.5 $start $range cv

set conc= 5 $start $range cv

set conc= 5.5 $start $range cv

set conc= 6 $start $range cv

set conc= 6.5 $start $range cv

set conc= 7 $start $range cv

set conc= 7.5 $start $range cv

set conc= 8 $start $range cv

set conc= 8.5 $start $range cv

set conc= 9 $start $range cv

set conc= 9.5 $start $range cv

set conc= 10 $start $range cv

set conc= 15 $start $range cv

set conc= 20 $start $range cv

set conc= 25 $start $range cv

set conc= 30 $start $range cv

set conc= 35 $start $range cv

set conc= 40 $start $range cv

set conc= 45 $start $range cv

set conc= 50 $start $range cv

set conc= 55 $start $range cv

set conc= 60 $start $range cv

set conc= 65 $start $range cv

set conc= 70 $start $range cv

set conc= 75 $start $range cv

set conc= 80 $start $range cv

set conc= 85 $start $range cv

set conc= 90 $start $range cv

set conc= 95 $start $range cv

set conc= 100 $start $range cv

set conc= 110 $start $range cv

set conc= 120 $start $range cv

set conc= 130 $start $range cv

set conc= 140 $start $range cv

set conc= 150 $start $range cv

set conc= 160 $start $range cv

set conc= 170 $start $range cv

set conc= 180 $start $range cv

set conc= 190 $start $range cv

set conc= 200 $start $range cv

set conc= 210 $start $range cv

set conc= 220 $start $range cv

set conc= 230 $start $range cv

set conc= 240 $start $range cv

set conc= 250 $start $range cv

set conc= 260 $start $range cv

end

proced inhal

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 39

set n=0

mouse

inhmet

mmouse

inhmet

end

proced cancer

prepar 'all

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168

set n=0

end

proced inhmet2

set conc= 0.015 $start $d aucl

set conc= 0.02 $start $d aucl

set conc= 0.025 $start $d aucl

set conc= 0.03 $start $d aucl

set conc= 0.035 $start $d aucl

set conc= 0.04 $start $d aucl

set conc= 0.045 $start $d aucl

set conc= 0.05 $start $d aucl

set conc= 0.055 $start $d aucl

set conc= 0.06 $start $d aucl

set conc= 0.065 $start $d aucl

set conc= 0.07 $start $d aucl

set conc= 0.075 $start $d aucl

set conc= 0.08 $start $d aucl

set conc= 0.085 $start $d aucl

set conc= 0.09 $start $d aucl

set conc= 0.095 $start $d aucl

set conc= 0.1 $start $d aucl

set conc= 0.15 $start $d aucl

set conc= 0.2 $start $d aucl

set conc= 0.25 $start $d aucl

set conc= 0.3 $start $d aucl

set conc= 0.35 $start $d aucl

set conc= 0.4 $start $d aucl

set conc= 0.45 $start $d aucl

set conc= 0.5 $start $d aucl

set conc= 0.55 $start $d aucl

set conc= 0.6 $start $d aucl

set conc= 0.65 $start $d aucl

set conc= 0.7 $start $d aucl

set conc= 0.75 $start $d aucl

set conc= 0.8 $start $d aucl

set conc= 0.85 $start $d aucl

set conc= 0.9 $start $d aucl

set conc= 0.95 $start $d aucl

set conc= 1 $start $d aucl

set conc= 1.5 $start $d aucl

set conc= 2 $start $d aucl

set conc= 2.5 $start $d aucl

set conc= 3 $start $d aucl
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 40

set conc= 3.5 $start $d aucl

set conc= 4 $start $d aucl

set conc= 4.5 $start $d aucl

set conc= 5 $start $d aucl

set conc= 5.5 $start $d aucl

set conc= 6 $start $d aucl

set conc= 6.5 $start $d aucl

set conc= 7 $start $d aucl

set conc= 7.5 $start $d aucl

set conc= 8 $start $d aucl

set conc= 8.5 $start $d aucl

set conc= 9 $start $d aucl

set conc= 9.5 $start $d aucl

set conc= 10 $start $d aucl

set conc= 15 $start $d aucl

set conc= 20 $start $d aucl

set conc= 25 $start $d aucl

set conc= 30 $start $d aucl

set conc= 35 $start $d aucl

set conc= 40 $start $d aucl

set conc= 45 $start $d aucl

set conc= 50 $start $d aucl

set conc= 55 $start $d aucl

set conc= 60 $start $d aucl

set conc= 65 $start $d aucl

set conc= 70 $start $d aucl

set conc= 75 $start $d aucl

set conc= 80 $start $d aucl

set conc= 85 $start $d aucl

set conc= 90 $start $d aucl

set conc= 95 $start $d aucl

set conc= 100 $start $d aucl

set conc= 110 $start $d aucl

set conc= 120 $start $d aucl

set conc= 130 $start $d aucl

set conc= 140 $start $d aucl

set conc= 150 $start $d aucl

set conc= 160 $start $d aucl

set conc= 170 $start $d aucl

set conc= 180 $start $d aucl

set conc= 190 $start $d aucl

set conc= 200 $start $d aucl

set conc= 0.015 $start $range cl

set conc= 0.02 $start $range cl

set conc= 0.025 $start $range cl

set conc= 0.03 $start $range cl

set conc= 0.035 $start $range cl

set conc= 0.04 $start $range cl

set conc= 0.045 $start $range cl

set conc= 0.05 $start $range cl

set conc= 0.055 $start $range cl

set conc= 0.06 $start $range cl

set conc= 0.065 $start $range cl

set conc= 0.07 $start $range cl

set conc= 0.075 $start $range cl

set conc= 0.08 $start $range cl
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 41

set conc= 0.085 $start $range cl

set conc= 0.09 $start $range cl

set conc= 0.095 $start $range cl

set conc= 0.1 $start $range cl

set conc= 0.15 $start $range cl

set conc= 0.2 $start $range cl

set conc= 0.25 $start $range cl

set conc= 0.3 $start $range cl

set conc= 0.35 $start $range cl

set conc= 0.4 $start $range cl

set conc= 0.45 $start $range cl

set conc= 0.5 $start $range cl

set conc= 0.55 $start $range cl

set conc= 0.6 $start $range cl

set conc= 0.65 $start $range cl

set conc= 0.7 $start $range cl

set conc= 0.75 $start $range cl

set conc= 0.8 $start $range cl

set conc= 0.85 $start $range cl

set conc= 0.9 $start $range cl

set conc= 0.95 $start $range cl

set conc= 1 $start $range cl

set conc= 1.5 $start $range cl

set conc= 2 $start $range cl

set conc= 2.5 $start $range cl

set conc= 3 $start $range cl

set conc= 3.5 $start $range cl

set conc= 4 $start $range cl

set conc= 4.5 $start $range cl

set conc= 5 $start $range cl

set conc= 5.5 $start $range cl

set conc= 6 $start $range cl

set conc= 6.5 $start $range cl

set conc= 7 $start $range cl

set conc= 7.5 $start $range cl

set conc= 8 $start $range cl

set conc= 8.5 $start $range cl

set conc= 9 $start $range cl

set conc= 9.5 $start $range cl

set conc= 10 $start $range cl

set conc= 15 $start $range cl

set conc= 20 $start $range cl

set conc= 25 $start $range cl

set conc= 30 $start $range cl

set conc= 35 $start $range cl

set conc= 40 $start $range cl

set conc= 45 $start $range cl

set conc= 50 $start $range cl

set conc= 55 $start $range cl

set conc= 60 $start $range cl

set conc= 65 $start $range cl

set conc= 70 $start $range cl

set conc= 75 $start $range cl

set conc= 80 $start $range cl

set conc= 85 $start $range cl

set conc= 90 $start $range cl

set conc= 95 $start $range cl
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 42

set conc= 100 $start $range cl

set conc= 110 $start $range cl

set conc= 120 $start $range cl

set conc= 130 $start $range cl

set conc= 140 $start $range cl

set conc= 150 $start $range cl

set conc= 160 $start $range cl

set conc= 170 $start $range cl

set conc= 180 $start $range cl

set conc= 190 $start $range cl

set conc= 200 $start $range cl

end

proced inhal2

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168

set n=0

mouse

inhmet2

mmouse

inhmet2

end

proced inhmet3

set conc= 0.015 $start $d aucsn

set conc= 0.02 $start $d aucsn

set conc= 0.025 $start $d aucsn

set conc= 0.03 $start $d aucsn

set conc= 0.035 $start $d aucsn

set conc= 0.04 $start $d aucsn

set conc= 0.045 $start $d aucsn

set conc= 0.05 $start $d aucsn

set conc= 0.055 $start $d aucsn

set conc= 0.06 $start $d aucsn

set conc= 0.065 $start $d aucsn

set conc= 0.07 $start $d aucsn

set conc= 0.075 $start $d aucsn

set conc= 0.08 $start $d aucsn

set conc= 0.085 $start $d aucsn

set conc= 0.09 $start $d aucsn

set conc= 0.095 $start $d aucsn

set conc= 0.1 $start $d aucsn

set conc= 0.15 $start $d aucsn

set conc= 0.2 $start $d aucsn

set conc= 0.25 $start $d aucsn

set conc= 0.3 $start $d aucsn

set conc= 0.35 $start $d aucsn

set conc= 0.4 $start $d aucsn

set conc= 0.45 $start $d aucsn

set conc= 0.5 $start $d aucsn

set conc= 0.55 $start $d aucsn

set conc= 0.6 $start $d aucsn

set conc= 0.65 $start $d aucsn

set conc= 0.7 $start $d aucsn

set conc= 0.75 $start $d aucsn
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 43

set conc= 0.8 $start $d aucsn

set conc= 0.85 $start $d aucsn

set conc= 0.9 $start $d aucsn

set conc= 0.95 $start $d aucsn

set conc= 1 $start $d aucsn

set conc= 1.5 $start $d aucsn

set conc= 2 $start $d aucsn

set conc= 2.5 $start $d aucsn

set conc= 3 $start $d aucsn

set conc= 3.5 $start $d aucsn

set conc= 4 $start $d aucsn

set conc= 4.5 $start $d aucsn

set conc= 5 $start $d aucsn

set conc= 5.5 $start $d aucsn

set conc= 6 $start $d aucsn

set conc= 6.5 $start $d aucsn

set conc= 7 $start $d aucsn

set conc= 7.5 $start $d aucsn

set conc= 8 $start $d aucsn

set conc= 8.5 $start $d aucsn

set conc= 9 $start $d aucsn

set conc= 9.5 $start $d aucsn

set conc= 10 $start $d aucsn

set conc= 15 $start $d aucsn

set conc= 20 $start $d aucsn

set conc= 25 $start $d aucsn

set conc= 30 $start $d aucsn

set conc= 35 $start $d aucsn

set conc= 40 $start $d aucsn

set conc= 45 $start $d aucsn

set conc= 50 $start $d aucsn

set conc= 55 $start $d aucsn

set conc= 60 $start $d aucsn

set conc= 65 $start $d aucsn

set conc= 70 $start $d aucsn

set conc= 75 $start $d aucsn

set conc= 80 $start $d aucsn

set conc= 85 $start $d aucsn

set conc= 90 $start $d aucsn

set conc= 95 $start $d aucsn

set conc= 100 $start $d aucsn

set conc= 110 $start $d aucsn

set conc= 120 $start $d aucsn

set conc= 130 $start $d aucsn

set conc= 140 $start $d aucsn

set conc= 150 $start $d aucsn

set conc= 160 $start $d aucsn

set conc= 170 $start $d aucsn

set conc= 180 $start $d aucsn

set conc= 190 $start $d aucsn

set conc= 200 $start $d aucsn

set conc= 0.015 $start $range csn

set conc= 0.02 $start $range csn

set conc= 0.025 $start $range csn

set conc= 0.03 $start $range csn

set conc= 0.035 $start $range csn
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 44

set conc= 0.04 $start $range csn

set conc= 0.045 $start $range csn

set conc= 0.05 $start $range csn

set conc= 0.055 $start $range csn

set conc= 0.06 $start $range csn

set conc= 0.065 $start $range csn

set conc= 0.07 $start $range csn

set conc= 0.075 $start $range csn

set conc= 0.08 $start $range csn

set conc= 0.085 $start $range csn

set conc= 0.09 $start $range csn

set conc= 0.095 $start $range csn

set conc= 0.1 $start $range csn

set conc= 0.15 $start $range csn

set conc= 0.2 $start $range csn

set conc= 0.25 $start $range csn

set conc= 0.3 $start $range csn

set conc= 0.35 $start $range csn

set conc= 0.4 $start $range csn

set conc= 0.45 $start $range csn

set conc= 0.5 $start $range csn

set conc= 0.55 $start $range csn

set conc= 0.6 $start $range csn

set conc= 0.65 $start $range csn

set conc= 0.7 $start $range csn

set conc= 0.75 $start $range csn

set conc= 0.8 $start $range csn

set conc= 0.85 $start $range csn

set conc= 0.9 $start $range csn

set conc= 0.95 $start $range csn

set conc= 1 $start $range csn

set conc= 1.5 $start $range csn

set conc= 2 $start $range csn

set conc= 2.5 $start $range csn

set conc= 3 $start $range csn

set conc= 3.5 $start $range csn

set conc= 4 $start $range csn

set conc= 4.5 $start $range csn

set conc= 5 $start $range csn

set conc= 5.5 $start $range csn

set conc= 6 $start $range csn

set conc= 6.5 $start $range csn

set conc= 7 $start $range csn

set conc= 7.5 $start $range csn

set conc= 8 $start $range csn

set conc= 8.5 $start $range csn

set conc= 9 $start $range csn

set conc= 9.5 $start $range csn

set conc= 10 $start $range csn

set conc= 15 $start $range csn

set conc= 20 $start $range csn

set conc= 25 $start $range csn

set conc= 30 $start $range csn

set conc= 35 $start $range csn

set conc= 40 $start $range csn

set conc= 45 $start $range csn

set conc= 50 $start $range csn
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 45

set conc= 55 $start $range csn

set conc= 60 $start $range csn

set conc= 65 $start $range csn

set conc= 70 $start $range csn

set conc= 75 $start $range csn

set conc= 80 $start $range csn

set conc= 85 $start $range csn

set conc= 90 $start $range csn

set conc= 95 $start $range csn

set conc= 100 $start $range csn

set conc= 110 $start $range csn

set conc= 120 $start $range csn

set conc= 130 $start $range csn

set conc= 140 $start $range csn

set conc= 150 $start $range csn

set conc= 160 $start $range csn

set conc= 170 $start $range csn

set conc= 180 $start $range csn

set conc= 190 $start $range csn

set conc= 200 $start $range csn

end

proced inhmet4

set conc= 0.015 $start $d aucbr

set conc= 0.02 $start $d aucbr

set conc= 0.025 $start $d aucbr

set conc= 0.03 $start $d aucbr

set conc= 0.035 $start $d aucbr

set conc= 0.04 $start $d aucbr

set conc= 0.045 $start $d aucbr

set conc= 0.05 $start $d aucbr

set conc= 0.055 $start $d aucbr

set conc= 0.06 $start $d aucbr

set conc= 0.065 $start $d aucbr

set conc= 0.07 $start $d aucbr

set conc= 0.075 $start $d aucbr

set conc= 0.08 $start $d aucbr

set conc= 0.085 $start $d aucbr

set conc= 0.09 $start $d aucbr

set conc= 0.095 $start $d aucbr

set conc= 0.1 $start $d aucbr

set conc= 0.15 $start $d aucbr

set conc= 0.2 $start $d aucbr

set conc= 0.25 $start $d aucbr

set conc= 0.3 $start $d aucbr

set conc= 0.35 $start $d aucbr

set conc= 0.4 $start $d aucbr

set conc= 0.45 $start $d aucbr

set conc= 0.5 $start $d aucbr

set conc= 0.55 $start $d aucbr

set conc= 0.6 $start $d aucbr

set conc= 0.65 $start $d aucbr

set conc= 0.7 $start $d aucbr

set conc= 0.75 $start $d aucbr

set conc= 0.8 $start $d aucbr

set conc= 0.85 $start $d aucbr

set conc= 0.9 $start $d aucbr
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 46

set conc= 0.95 $start $d aucbr

set conc= 1 $start $d aucbr

set conc= 1.5 $start $d aucbr

set conc= 2 $start $d aucbr

set conc= 2.5 $start $d aucbr

set conc= 3 $start $d aucbr

set conc= 3.5 $start $d aucbr

set conc= 4 $start $d aucbr

set conc= 4.5 $start $d aucbr

set conc= 5 $start $d aucbr

set conc= 5.5 $start $d aucbr

set conc= 6 $start $d aucbr

set conc= 6.5 $start $d aucbr

set conc= 7 $start $d aucbr

set conc= 7.5 $start $d aucbr

set conc= 8 $start $d aucbr

set conc= 8.5 $start $d aucbr

set conc= 9 $start $d aucbr

set conc= 9.5 $start $d aucbr

set conc= 10 $start $d aucbr

set conc= 15 $start $d aucbr

set conc= 20 $start $d aucbr

set conc= 25 $start $d aucbr

set conc= 30 $start $d aucbr

set conc= 35 $start $d aucbr

set conc= 40 $start $d aucbr

set conc= 45 $start $d aucbr

set conc= 50 $start $d aucbr

set conc= 55 $start $d aucbr

set conc= 60 $start $d aucbr

set conc= 65 $start $d aucbr

set conc= 70 $start $d aucbr

set conc= 75 $start $d aucbr

set conc= 80 $start $d aucbr

set conc= 85 $start $d aucbr

set conc= 90 $start $d aucbr

set conc= 95 $start $d aucbr

set conc= 100 $start $d aucbr

set conc= 110 $start $d aucbr

set conc= 120 $start $d aucbr

set conc= 130 $start $d aucbr

set conc= 140 $start $d aucbr

set conc= 150 $start $d aucbr

set conc= 160 $start $d aucbr

set conc= 170 $start $d aucbr

set conc= 180 $start $d aucbr

set conc= 190 $start $d aucbr

set conc= 200 $start $d aucbr

set conc= 210 $start $d aucbr

set conc= 220 $start $d aucbr

set conc= 230 $start $d aucbr

set conc= 240 $start $d aucbr

set conc= 250 $start $d aucbr

set conc= 260 $start $d aucbr

set conc= 0.015 $start $range cbr

set conc= 0.02 $start $range cbr
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 47

set conc= 0.025 $start $range cbr

set conc= 0.03 $start $range cbr

set conc= 0.035 $start $range cbr

set conc= 0.04 $start $range cbr

set conc= 0.045 $start $range cbr

set conc= 0.05 $start $range cbr

set conc= 0.055 $start $range cbr

set conc= 0.06 $start $range cbr

set conc= 0.065 $start $range cbr

set conc= 0.07 $start $range cbr

set conc= 0.075 $start $range cbr

set conc= 0.08 $start $range cbr

set conc= 0.085 $start $range cbr

set conc= 0.09 $start $range cbr

set conc= 0.095 $start $range cbr

set conc= 0.1 $start $range cbr

set conc= 0.15 $start $range cbr

set conc= 0.2 $start $range cbr

set conc= 0.25 $start $range cbr

set conc= 0.3 $start $range cbr

set conc= 0.35 $start $range cbr

set conc= 0.4 $start $range cbr

set conc= 0.45 $start $range cbr

set conc= 0.5 $start $range cbr

set conc= 0.55 $start $range cbr

set conc= 0.6 $start $range cbr

set conc= 0.65 $start $range cbr

set conc= 0.7 $start $range cbr

set conc= 0.75 $start $range cbr

set conc= 0.8 $start $range cbr

set conc= 0.85 $start $range cbr

set conc= 0.9 $start $range cbr

set conc= 0.95 $start $range cbr

set conc= 1 $start $range cbr

set conc= 1.5 $start $range cbr

set conc= 2 $start $range cbr

set conc= 2.5 $start $range cbr

set conc= 3 $start $range cbr

set conc= 3.5 $start $range cbr

set conc= 4 $start $range cbr

set conc= 4.5 $start $range cbr

set conc= 5 $start $range cbr

set conc= 5.5 $start $range cbr

set conc= 6 $start $range cbr

set conc= 6.5 $start $range cbr

set conc= 7 $start $range cbr

set conc= 7.5 $start $range cbr

set conc= 8 $start $range cbr

set conc= 8.5 $start $range cbr

set conc= 9 $start $range cbr

set conc= 9.5 $start $range cbr

set conc= 10 $start $range cbr

set conc= 15 $start $range cbr

set conc= 20 $start $range cbr

set conc= 25 $start $range cbr

set conc= 30 $start $range cbr

set conc= 35 $start $range cbr
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 48

set conc= 40 $start $range cbr

set conc= 45 $start $range cbr

set conc= 50 $start $range cbr

set conc= 55 $start $range cbr

set conc= 60 $start $range cbr

set conc= 65 $start $range cbr

set conc= 70 $start $range cbr

set conc= 75 $start $range cbr

set conc= 80 $start $range cbr

set conc= 85 $start $range cbr

set conc= 90 $start $range cbr

set conc= 95 $start $range cbr

set conc= 100 $start $range cbr

set conc= 110 $start $range cbr

set conc= 120 $start $range cbr

set conc= 130 $start $range cbr

set conc= 140 $start $range cbr

set conc= 150 $start $range cbr

set conc= 160 $start $range cbr

set conc= 170 $start $range cbr

set conc= 180 $start $range cbr

set conc= 190 $start $range cbr

set conc= 200 $start $range cbr

set conc= 210 $start $range cbr

set conc= 220 $start $range cbr

set conc= 230 $start $range cbr

set conc= 240 $start $range cbr

set conc= 250 $start $range cbr

set conc= 260 $start $range cbr

end

proced inhal3

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168

set n=0

mouse

inhmet3

mmouse

inhmet3

set tstop=144

set n=0

mouse

inhmet

inhmet3

end

proced inhalneuro

set hvdprn=.f.

ccl2ccl

SET VMCH=2200, FCH=10800

SET TEXPOS=24, TCHNG=170, TSTOP=24, week=168

set n=0

rat

set bw=0.226
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 49

inhmet

inhmet4

set bw=0.168

inhmet

inhmet4

end

proced immunSA

set hvdprn=.f.

CCL2CCL

SET VMCH=2200, FCH=10800

SET TEXPOS=24, TCHNG=170, TSTOP=168, week=168

set CONC= 0.75

fmsa3

SET CONC=0.7575 $START $ D aucsn, DM1 $set CONC=0.75

$START $ D AUCsn, DM1

set tstop=144

fmsa3

SET CONC=0.7575 $START $ D AUCsn, DM1 $set CONC=0.75

$START $ D AUCsn, DM1

set conc=0.032

set tstop=168

fmsa3

SET CONC=0.03232 $START $ D AUCsn, DM1 $set CONC=0.032

$START $ D AUCsn, DM1

set tstop=144

fmsa3

SET CONC=0.03232 $START $ D AUCsn, DM1 $set CONC=0.032

$START $ D AUCsn, DM1

END
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 50

EXHSIR.CSL

PROGRAM: PHYSIOLOGICAL PHARMACOKINETIC MODEL -- WITH DATA (EXH.CSL)

'Model to examine gas phase elimination rate data'

'M. L. Gargas 16 OCT 1987 .......................'

 'Revised 4/16/01 by Lisa M. Sweeney, adding brain, qsc, vsc'

'qpc and qcc scaling changed to 0.7'

 'suicide enzyme inhib and resynthesis added 12/14/01 LMS'

INITIAL 

 

 

CONSTANT QPC = 14. $'Alveolar ventilation rate (l/hr)'

CONSTANT QCC = 14. $'Cardiac output (l/hr)'

CONSTANT QLC = 0.25 $'Fractional blood flow to liver'

CONSTANT QFC = 0.09 $'Fractional blood flow to fat'

CONSTANT QSC = 0.336 $'Fractional blood flow to slowly perf'

CONSTANT QSNC = 0.011 $'Fractional blood flow to spleen'

CONSTANT Qbrc = 0.02 $'Fractional blood flow to brain'

CONSTANT BW = 0.22 $'Body weight (kg)'

CONSTANT VLC = 0.04 $'Fraction liver tissue'

CONSTANT VFC = 0.07 $'Fraction fat tissue'

CONSTANT VSC = 0.5946 $'Fraction of slowly perfused tissue'

CONSTANT VSNC = 0.0035 $'Fraction of spleen'

CONSTANT VBRC = 0.0057 $'Fraction of brain tissue'

CONSTANT VRC = 0.2235 $'Fraction of richly perfused tissue'

CONSTANT PLA = 3.46 $'Liver/air partition coefficient'

CONSTANT PFA = 86.5 $'Fat/air partition coefficient'

CONSTANT PSA = 1.16 $'Slowly perfused tissue/air partition'

CONSTANT PRA = 3.46 $'Richly perfused tissue/air partition'

CONSTANT PSNA = 1 $'Spleen/air partition'

CONSTANT PBRA = 3.46 $'brain/air partition'

CONSTANT PB = 40.2 $'Blood/air partition coefficient'

CONSTANT MW = 133.14 $'Molecular weight (g/mol)'

CONSTANT VMAXC = 8.36 $'Maximum velocity of metabolism (mg/hr-1kg) in liver'

CONSTANT VMAXRC = 0 $'Maximum velocity of metabolism (mg/hr-1kg) in rpt'

CONSTANT KM = 0.36 $'Michaelis-Menten constant (mg/l)'

CONSTANT KFC = 0. $'First order metabolism rate constant (/hr-1kg)'

CONSTANT Kdet=0.025 $'rate of enzyme turnover (/hr)'

CONSTANT Kdes=0 $'rate of enzyme activity loss thru inhibition by ES mech'

Constant kdte=0 $'rate of enzyme activity loss thru inhibition by TE mech'

Constant kdfe=0 $'rate of enzyme activity loss thru inhibition by FE mech'

Constant kdbi=0 $'rate of enzyme activity loss thru inhibition by BI mech'

CONSTANT CONC = 1000. $'Inhaled concentration (ppm)'

CONSTANT VMCH = 2.2 $'VOLUME OF METABOLISM CHAMBER (L)'

CONSTANT FCH = 10.7 $'FLOW THROUGH METABOLISM CHAMBER (L/HR)'

CONSTANT N = 1. $'NUMBER OF RATS IN METABOLISM CHAMBER'

CONSTANT ABG0=10.0 $'TOTAL BACKGROUND AMT FROM FUR (MG)'

CONSTANT KBG = 0.0 $'RATE OF FUR OFF-GASING (/HR)'

 

 'Timing commands'
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 51

 

CONSTANT TSTOP = 24. $'Length of experiment (hrs)'

CONSTANT TEXPOS = 6 $'Length of open chamber exposure'

CONSTANT WEEK=120. $'exposure only on week days'

CONSTANT TCHNG = 168. $'Length of inhalation exposure (hrs)'

CONSTANT POINTS = 24. $'Number of points in plot'

 CINT = texpos/POINTS $'Communication interval'

 CHNG = TCHNG - 0.00001

 

 VMC = VMCH - N*BW $'NET METABOLISM CHAMBER VOLUME (L)'

 'Scaled parameters'

 

 QC = QCC*BW**0.70

 QP = QPC*BW**0.70

 QL = QLC*QC

 QF = QFC*QC

 QS = qsc*QC

 qsn = qsnc*qc

 QBR = qbrc*QC

 QR = QC-(QL+QF+QS+QBR+QSN)

 VL = VLC*BW

 VF = VFC*BW

 VS = vsc*BW

 vsn = vsnc*bw

 VR = vrc*BW

VBR = VBRC*BW

 VMAX = VMAXC*BW**0.7

 VMAXR= VMAXRC*BW**0.7

 KF = KFC/BW**0.3

PF = PFA/PB $PL =PLA/PB $PR=PRA/PB $PS= PSA/PB $ PBR=PBRA/PB $ PSN=PSNA/PB

 CII = 0.0

END $'End of initial' 

 

DYNAMIC 

 

ALGORITHM IALG = 2 $'Gear method for stiff systems'

 

DERIVATIVE 

 CI = PULSE(0., 24., TEXPOS)*PULSE(0.,168., WEEK)*CONC*MW/24450

 'Amount inhaled'

 RAI = QP*CI

AI = INTEG(RAI,0.)

 

 'CA = Concentration in arterial blood (mg/l)'

 CA = (QC*CV+QP*(CI+CII*CCH))/(QC+(QP/PB))

 AUCB = INTEG(CA,0.)

 

 'AX = Amount exhaled (mg)' 

 CX = CA/PB 

 CXPPM = (0.7*CX+0.3*CI)*24450./MW

 RAX = QP*CX 

 AX = INTEG(RAX, 0.)

 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 52

 'ACH = AMOUNT IN METABOLISM CHAMBER (MG/L)'

 RACH = N * CII* QP * (CX-CCH) - CII*FCH*CCH - RABG 

 ACH = INTEG(RACH,0.)

 CCH = ACH/VMC 

 PPMOUT = CCH*24450./MW

 RATE1 = FCH*CCH

 TOTAL = INTEG(RATE1,0.0)

 

 'ABG = AMT OF BACKGROUND CONC FROM FUR'

 RABG = -KBG*ABG*STEP(TCHNG)

 ABG = INTEG(RABG,ABG0)

 'AS = Amount in slowly perfused tissues (mg)'

 RAS = QS*(CA-CVS)

 AS = INTEG(RAS,0.)

 CVS = AS/(VS*PS)

 CS = AS/VS 

 

 'ASN = Amount in spleen (mg)'

 RASN = QSN*(CA-CVSN)

 ASN = INTEG(RASN,0.)

 CVSN = ASN/(VSN*PSN)

 CSN = ASN/VSN 

 AUCSN = INTEG(CSN,0.)

 'AR = Amount in rapidly perfused tissues (mg)' 

 RAR = QR*(CA-CVR) - RAMR

 AR = INTEG(RAR,0.)

 CVR = AR/(VR*PR)

 CR = AR/VR 

 

 'ABR = Amount in brain(mg)' 

 RABR = QBR*(CA-CVBR)

 ABR = INTEG(RABR,0.)

 CVBR = ABR/(VBR*PBR)

 CBR = ABR/VBR 

 aucbr= integ(cbr, 0.)

 

 'AF = Amount in fat tissue (mg)'

 RAF = QF*(CA-CVF) 

 AF = INTEG(RAF,0.)

 CVF = AF/(VF*PF)

 CF = AF/VF 

 

 'AL = Amount in liver tissue (mg)'

 RAL = QL*(CA-CVL) - RAML 

 AL = INTEG(RAL,0.)

 CVL = AL/(VL*PL)

 CL = AL/VL 

 AUCL = INTEG(CL,0.)

 

 'VMT = maximal rate of metabolism'

 RVMT = (VMAX-VMT)*KDET-KDES*RAML*RAML-KDTE*RAML*VMT ...

 -KDFE*RAML*VMT*KM/(KM+ CVL)-KDBI*RAML

 VMT = INTEG(RVMT, VMAX)

 'AM = Amount metabolized (mg)' 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 53

 RAML = (VMT*CVL)/(KM+CVL) + KF*CVL*VL 

 RAMR = (VMAXR*CVR)/(KM+CVR) 

 RAM = RAML + RAMR

 AM = INTEG(RAM, 0.)

 AML = INTEG(RAML,0)

 DM1=AML/VL

 

 

 'CV = Mixed venous blood concentration (mg/l)' 

 CV = (QF*CVF + QL*CVL + QS*CVS + QR*CVR + QBR*CVBR +QSN*CVSN)/QC 

 AUCV = INTEG(CV,0.)

 

 'TMASS = mass balance (mg)' 

 TMASS = AF+AL+AS+AR+AM+ABR+ASN+AX

 

 'DOSEX = Net amount absorbed (mg)'

 DOSEX = AI+AX

 

 TERMT(T.GE.TSTOP) 

 

 

END $'End of derivative'

 

IF (T.GE.CHNG) CI=0. 

IF (T.GE.CHNG) CII=1.0 

END $'End of dynamic' 

 

END $'End of program'

 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 54

APPENDIX B

ROUTE-TO-ROUTE EXTRAPOLATION FOR 1,1,2-TCE IN VENOUS BLOOD

(PEAK CONCENTRATION AND AUC), BRAIN AUC, AND AMOUNT

METABOLIZED IN THE LIVER 

Equivalent inhaled concentrations, based on blood concentrations (peak or AUC), brain

AUC, or amount metabolized in liver predicted by the PBPK models, are provided in Table

B-1. Mechanistic evidence indicates that peak concentration in the brain is the most

appropriate dose metric for route-to-route extrapolation (provided in the main report), but

route-to-route extrapolation results for other specified endpoints are provided, as specified

in the ECA. 

Table B-1.

Inhaled Concentrations Equivalent to the Rat Acute Neurotoxicity NOAEL and

LOAEL based on ECA-Specified Dose Metrics

Oral Dose

mg/kg

Sex Peak

Blood

AUC

Blood

AUC Brain Amount

metabolized

(liver)

95 (NOAEL) Female 167 ppm 43 ppm 36 ppm 32 ppm

200 (LOAEL) Female 248 ppm 147 ppm 139 ppm 50 ppm

95 (NOAEL) Male 174 ppm 52 ppm 43 ppm 34 ppm

200 (LOAEL) Male 260 ppm 154 ppm 147 ppm 52 ppm

The value of the “equivalent” inhaled concentration was dependent on the choice of internal

dose metric. For example, the inhalation “equivalent” of 95 mg/kg by corn oil gavage to a

male rat ranged from 34 ppm, based on amount metabolized, to 174 ppm, based on peak

blood concentration. In general, the predicted concentration of a compound in a wellperfused, non-metabolizing tissue that is not a portal of entry will track the concentration in

the blood (i.e., tissue concentration . blood concentration × tissue:blood partition

coefficient). Such is the case for brain, and the route-to-route extrapolation results do not

differ substantially if based on blood rather than brain concentrations. 
1,1,2-TCE Acute Neurotoxicity Route-to-Route November 29, 2004

Page 55

APPENDIX C

GRAPHICAL PRESENTATION OF ROUTE-TO-ROUTE EXTRAPOLATION

FOR 1,1,2-TCE IN RATS

In the figures provided below, the dose metrics were determined over a single day of

exposure. Figures C-1 and C-2 present the route-to-route extrapolation curves for all dose

metrics for female and male rats, respectively. In Figures C-1 and C-2, one can clearly see

that the some of the route-to-route-extrapolation curves for the different dose metrics cross.

Thus, in the absence of empirical or mechanistic information supportive of a particular dose

metric, the choice of the most “conservative” dose metric for route-to-route extrapolation

may depend on the dose from which one starts. 
1,1,2-

TCE Acute Neurotoxicity RoutetoRouteNovember 29, 2004

Page 56