PHYSIOLOGICALLY BASED MODELING OF HALON REPLACEMENTS FOR HUMAN 

SAFETY EVALUATION 

Allen Vinegar and Gary W. Jepson 

Air Force Research Laboratory/Operational Toxicology Branch (AFRL/HEST) – ManTech 

Environmental Technology, Inc. 

Next-Generation Fire Suppression Technology Program (NGP) 

Project 3B/1/89 

Final Report – Section I of II 

This research is part of the Department of Defense’s Next-Generation Fire Suppression Technology 

Program, funded by the DoD Strategic Environmental Research and Development Program 

(SERDP) 
2 

TABLE OF CONTENTS 

Page 

GENERAL INTRODUCTION.....................................................................................4 

REQUIREMENTS FOR CONDUCTING MONTE CARLO SIMULATIONS FOR ESTABLISHING 

 SAFE EXPOSURE TIMES FOR POTENTIAL HALON REPLACEMENTS AGENTS.................5 

SETTING SAFE ACUTE EXPOSURE LIMITS FOR HALON REPLACEMENT CHEMICALS 

 USING PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING..........................10 

Abstract.................................................................................................11 

Introduction.............................................................................................12 

Methods.................................................................................................13

Results...................................................................................................15 

Discussion.............................................................................................16 

Acknowledgments.....................................................................................19 

 References.............................................................................................20 

Table I – Parameter Distributions for Monte Carlo Analysis...................................25 

Table II – Partition Coefficients....................................................................26 

Table III – Acceptable Human Exposure Times for Halon 1301..............................27 

Table IV – Acceptable Human Exposure Times for CF3I......................................27 

Table V – Acceptable Human Exposure Times for HFC-125.................................27 

Table VI – Acceptable Human Exposure Times for HFC-227ea.............................28 

Table VII – Acceptable Human Exposure Times for HFC-236fa.............................28 

Figure Legends.......................................................................................29 

Figures............................................................................................31-33 

 MODELING CARDIAC SENSITIZATION POTENTIAL OF HUMANS EXPOSED TO HALON 

 1301 OR HALON 1211 ABOARD AIRCRAFT...............................................................34 

Abstract..............................................................................................35 

Introduction..........................................................................................36 

Materials and Methods..............................................................................38 

 Results................................................................................................39 
3 

TABLE OF CONTENTS (continued)

Page 

Figures...........................................................................................42-51 

Discussion...........................................................................................52 

Acknowledgments..................................................................................52 

Literature Cited....................................................................................53 

PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR SIMULATING BREATHBY-BREATH INHALATION................................................................55 

Program.............................................................................................56 

 Appendix: Setup File for Performing Monte-Carlo Simulation Using ACSL-TOX 

 Software.....................................................................64 

Appendix: Sample M File for conducting Monte-Carlo Simulation for Halon 1301.....66 
4 

GENERAL INTRODUCTION 

This section of the final report contains several parts. The first part describes the necessary 

requirements for enabling one to conduct simulations for assessing safe exposure times. These 

requirements involve chemical specific data necessary for running the model and biological data 

collection for validating the model. The second part demonstrates the use of the model in setting 

acute exposure limits for Halon 1301 and four potential replacement candidates: CF3I, HFC-125, 

HFC-227ea, and HFC-236fa. This part has been submitted to the journal Inhalation Toxicology

and has been accepted for publication. The third part makes use of published data on releases of 

Halon 1301 and Halon 1211 in aircraft. These data are used to demonstrate whether in the 

scenarios presented there would be any potential hazard for individuals being exposed under the 

stated conditions. This part will be submitted to the journal Aviation, Space, and Environmental 

Medicine. Finally, the fourth part presents a listing of the actual code for the physiologically 

based pharmacokinetic model used for simulating short–term exposures to halogenated 

hydrocarbons. This code, as it stands, is written to run with the Advanced Continuous Simulation 

Language package called ACSL-TOX. The distributor for this software is Pharsight Corporation, 

Mountain View, CA.
5 

Requirements for Conducting Monte Carlo Simulations for Establishing 

Safe Exposure Times for Potential Halon Replacement Agents 

Allen Vinegar and *

Gary W. Jepson 

AFRL/HEST 

ManTech Environmental Technology Inc. 

P.O. Box 31009 

Dayton, OH 45437 

*

Current address of G.W. Jepson - 

E. I. Du Pont de Nemours and Company 

Haskell Laboratory for Toxicology 

And Industrial Medicine 

1090 Elkton Rd., P.O. Box 50 

Newark, DE 19714 
6 

The procedures for determining safe exposure time involve using a physiologically based 

pharmacokinetic (PBPK) model to determine the arterial blood concentration associated with a 

potential human exposure to a chemical agent and comparing it with the arterial blood 

concentration attained by a dog exposed to that agent after five minutes of exposure at the lowest 

observable adverse effect level (LOAEL) for cardiac sensitization (Vinegar and Jepson, 1996; 

Vinegar et al., (in press)). In order to make these determinations for any chemical agent the 

following chemical specific information is needed: 1 - cardiac sensitization LOAEL determined 

in beagle dogs, 2 - arterial concentration measured after five minutes of exposure of beagles to 

the LOAEL concentration, 3 - partition coefficients of the chemical in blood, liver, fat, and 

muscle from rat, 4 - metabolic constants (determined from gas uptake studies using rats), 5 - 

partition coefficients of the chemical in human blood (partitions measured using human liver, fat, 

and muscle would be desirable but not necessary). A validated PBPK model capable of tracking 

ventilation on a breath-by-breath basis is needed for performing the simulations (Vinegar et al., 

1998). The model must be capable of running under a system that allows the performance of 

Monte Carlo simulations. 

1 – Cardiac sensitization LOAEL determined in beagle dogs. 

The standard for evaluating exposure to agents that might potentially evoke a cardiac 

sensitization response is the cardiac sensitization test performed in beagle dogs (Dodd and 

Vinegar, 1998). The results of this test are expressed in terms of the lowest observed adverse 

effect level (LOAEL) and no observed adverse effect level (NOAEL). The LOAEL value is used 

as the target value for the PBPK assessment of safe exposure time. One of the problems is how 

far apart the LOAEL and NOAEL values are from each other. This is a function of the step size 

in concentration used for the cardiac sensitization test. The expense of the test often prevents a 

small increment from being used. 

2 – Arterial concentration measured after five minutes of exposure of beagles to the LOAEL 

concentration. 

The arterial concentration attained by a beagle after five minutes of exposure is taken as the 

target with which to compare a human exposure simulation. Attaining this information requires 

that studies be done with beagles that have been cannulated for the sampling of arterial blood. At 

least six beagles should be exposed, without epinephrine challenge, at three exposure 

concentrations for 10 minutes at each exposure. The concentrations should be the LOAEL, 

approximately 25% above the LOAEL, and approximately 25k% below the LOAEL. Blood 

samples should be taken at least at 1, 2, 5, 7, and 10 minutes. The five minute time point is most 

critical as it provides the target arterial concentration. Multiple sample points and exposure 

concentrations are necessary to check the reliability of the data obtained. The volatility and low 

biological tissue solubility of these chemicals produce challenges for accurate data collection and 

analysis. Prior to performing the exposures, tests should be done on the material to be used for 

arterial cannulation. The materials used in the manufacture of cannulas often absorb chemicals. 

A cannula that is inert with respect to one chemical may not be so for another. Furthermore, even 

if the solubility is low in the cannula, the tissue solubility may be in the same order of magnitude 

or lower. Therefore, as blood is drawn it may give up chemical to or take up chemical from the 

cannula depending on the concentration gradient. Sampling at multiple time points gives 
7 

information about expected pharmacokinetic behavior. If the data don’t conform to expected 

behavior, the reliability of the five-minute point is called into question. Performing exposures at 

three concentrations also allows observation of expected relationships in blood concentration vs. 

time of sampling vs. exposure concentration. It is important that the laboratory performing these 

studies be aware of and know how to conduct experiments in light of these problems. 

3 - Partition coefficients of the chemical in blood, liver, fat, and muscle from rat. 

One of the basic chemical specific requirements for the PBPK model is solubility in tissues. 

Standard techniques have been published for determining solubility or partition coefficients of 

volatile chemicals (Gargas et al., 1989). However, this method depends upon a difference 

measurement as part of the methodology. Partition coefficients of chemicals of low solubility, 

such as many of the halon replacements candidates, can not be accurately measured by this 

method. Instead, a method using direct measurements such as the direct tonometry method 

described by Eger (1987) and Lerman et al. (1985 and 1986) must be used instead. A 

modification of this method is currently being addressed in our laboratory. The published method 

uses homogenized tissue. We find that non-uniform homogenization and sticking of tissue to 

glass with resulting loss results in variable data. Our modification uses whole tissue pieces. 

4 - Metabolic constants (determined from gas uptake studies using rats). 

The other chemical specific data needed for running a PBPK model are the metabolic constants. 

These are obtained using a gas uptake method as described by Gargas et al. (1986). Fortunately, 

most of the proposed halon replacements are relatively inert and have extremely low to no 

measurable metabolism. Furthermore, even with moderate metabolism, there is no noticeable 

effect on the outcome of short-term simulations required for modeling of cardiac sensitization. 

5 - Partition coefficients of the chemical in human blood (partitions measured using human liver, 

fat, and muscle would be desirable but not necessary). 

The most sensitive parameter for determination of the correct blood concentration is the blood 

partition coefficient. Therefore since the model is being used to simulate human exposures, 

human blood partition coefficients must be measured. For short term simulations the model is 

almost insensitive to differences in the other partitions. Since human blood partitions often differ 

by as much as two-fold from rat blood partitions it is necessary to make the human blood 

measurements. Other tissue partitions tend not to differ as much. However, if human tissue is 

available then the tissue partitions should be determined. Statements concerning methodology 

under 3 above, apply to this section also. 

Model validation. 
8 

After obtaining partition coefficients and determining metabolic constants for a chemical it is 

necessary to collect data to demonstrate that the model is capable of simulating exposures to the 

chemical. Since the initial model is constructed using rat partition coefficients and rat metabolic 

constants, pharmacokinetic data should be collected from at least six rats that have been exposed 

by inhalation to the chemical. Typically, the exposure should be for an hour with an hour postexposure for sampling during the off gassing of the chemical. Validation using only blood 

requires a minimum number of animals since blood can be serially sampled. However, validation 

for tissue concentrations requires serial sacrificing of animals during and after the exposure. The 

total number of animals would then be six times the number of time points sampled (minimally 

five during exposure and five post-exposure). Only seldom are there human data for a direct 

validation of the human model. For new agents the likelihood of obtaining human data is 

negligible. 
9 

Literature Cited 

Dodd, E.E. and A. Vinegar. 1998. Cardiac sensitization testing of the halon replacement 

candidates trifluoroiodomethane (CF3I) and 1,1,2,2,3,3,3-heptafluoro-1-iodopropane (C3F7I). 

Drug Chem. Toxicol. 21:137-149. 

Eger, E.I. 1987. Partition coefficients of I-653 in human blood, saline, and olive oil. Anesth. 

Analg. 66:971-973. 

Gargas, M.L., M.E. Andersen, and H.J. Clewell, III. 1986. A physiologically-based simulation 

approach for determining metabolic constants from gas uptake data. Toxicol. Appl. Pharmacol. 

86:341-352. 

Gargas, M.L., R.J. Burgess, D.E. Voisard, G.H. Cason, and M.E. Andersen. 1989. Partition 

coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol. 

Appl. Pharmacol. 98:87-99. 

Lerman, J., G.A. Gregory, M.M. Willis, B.I. Schmidt, and E.I. Eger. 1985. Age and the solubility 

of volatile anesthetics in ovine tissues. Anesth. Analg. 64:1097-1100. 

Lerman, J. G.A. Gregory, M.M. Willis, B.I. Schmidt-Bantel, and E.I. Eger. 1986. Effect of age 

on the solubility of volatile anesthetics in human tissues. Anesth. Analg. 65:307-311. 

Vinegar, A. and G.W. Jepson. 1996. Cardiac sensitization thresholds of halon replacement 

chemicals predicted in humans by physiologically based pharmacokinetic modeling. Risk Anal. 

16:571-579. 

Vinegar, A., G.W. Jepson, M. Cisneros, R. Rubenstein, and W. J. Brock. (in press). Setting safe 

acute exposure limits for halon replacement chemicals using physiologically-based 

pharmacokinetic modeling. Inhal. Toxicol. 

Vinegar, A. G.W. Jepson, and J.H. Overton. 1998. PBPK modeling of short-term (0 to 5 min) 

human inhalation exposures to halogenated hydrocarbons. Inhal. Toxicol. 10:411-429. 
10 

SETTING SAFE ACUTE EXPOSURE LIMITS FOR HALON REPLACEMENT 

CHEMICALS USING PHYSIOLOGICALLY-BASED PHARMACOKINETIC 

MODELING 

ALLEN VINEGAR, GARY W. JEPSON1

 

AFRL/HEST, ManTech Environmental Technology, WPAFB, OH 45433

MARK CISNEROS 

Great Lakes Chemical Corporation, W. Lafeyette, IN 47905

REVA RUBENSTEIN 

U.S. Environmental Protection Agency, Washington, DC 20460

WILLIAM J. BROCK2

The DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE 19714

Safe Exposure Limits For Halon Replacements 

Address all Correspondence to: 

Allen Vinegar 

ManTech Environmental Technology, Inc. 

P.O. Box 31009 

Dayton, OH 45437 

Phone: 937-255-5150 x3145 Fax: 937-258-2197 

Email: allen.vinegar@he.wpafb.af.mil 

 

1

 Current Address: The DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE 

2

 Current Address: Unilever Research-U.S., Edgewater, NJ 
11 

Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. 

The acute toxic endpoint of concern for these agents is cardiac sensitization. An approach is 

described which links the cardiac endpoint as assessed in dogs to a target arterial concentration 

in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. 

Monte Carlo simulations, which account for population variability, were used to establish safe 

exposure times at different exposure concentrations for Halon 1301 (bromotrifluoromethane), 

CF3I (trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-

heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). Application of the 

modeling technique herein described not only makes use of the conservative cardiac sensitization 

endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better 

establish standards for safe exposure. The combined application of cardiac sensitization data and 

physiologically based modeling provides a quantitative approach, which can facilitate the 

selection and effective use of halon replacement candidates. 

Key Words: Cardiac Sensitization, Halon Replacement Chemicals, Physiologically Based 

Pharmacokinetic Modeling, Safe Exposure Limits, Humans, Halon 1301, CF3I, HFC-125, HFC227ea, HFC-236fa 
12 

INTRODUCTION 

 Many, if not most, of the proposed replacements for Halon 1301 in fire suppression 

applications are halogenated hydrocarbons. As a group, acute exposure to the halogenated 

hydrocarbons has been associated with the ability to reversibly increase the sensitivity of the 

heart to epinephrine (Reinhardt, 1971; Mullin, 1979). Consequently cardiac sensitization has 

been of keen interest to regulatory authorities for setting guidelines for human exposure to these 

agents because the use of these agents involves potentially acute high concentration exposure. 

Vinegar and Jepson (1996) outlined a procedure for setting exposure limits for halon 

replacement chemicals using physiologically-based pharmacokinetic (PBPK) modeling to predict 

blood levels associated with the potential onset of a cardiac sensitization response. The approach 

outlined by Vinegar and Jepson links the laboratory data that are generated from a routine 

cardiac sensitization toxicity test in dogs to relevant events occurring for humans exposed to 

potential cardiac sensitizers. The LOAEL (lowest observed adverse effect level) for cardiac 

sensitization in beagle dogs is determined by inhalation exposure to the chemical of interest and 

challenging intravenously with epinephrine levels well above physiological levels. Therefore, the 

test is considered conservative and the resulting LOAEL is used without any correction factors. 

The epinephrine challenge is given five minutes into the exposure. That the effect is due to the 

peak concentration of chemical rather than area under the curve (AUC) has been established 

(Reinhardt et al., 1971). Thus, the arterial concentration at five minutes is the target arterial 

concentration or dose metric that is associated with the potential for cardiac sensitization. 

Different exposure concentration scenarios can then be modeled using the PBPK model. The 

time required for an arterial concentration to reach the LOAEL target arterial concentration could 

be considered the safe (i.e., protective) exposure duration. 
13 

 Variability in human physiological parameters should be considered in determining safe 

exposure times. Others have used Monte Carlo simulations to describe the effect of 

interindividual variability on the output of PBPK models (Bois et al., 1991; Bois and Paxman, 

1992; Clewell and Jarnot, 1994; Cronin et al., 1995; Farrar et al., 1989, Hetrick et al., 1991; 

Portier and Kaplan, 1989; Simon, 1997; Spear et al., 1991; Thomas et al., 1996a&b; Yang et al., 

1995). However, none of these studies involved predicting short-term (0 to 5 min) effects. This 

paper describes the methods developed for determining short-term safe exposure times for halon 

replacement candidates using Monte Carlo simulations to account for variability and presents the 

results for Halon 1301 (bromotrifluoromethane) and four potential replacement chemicals CF3I 

(trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-

heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). 

METHODS 

 

Target Arterial Concentrations of Chemical in Blood 

 Arterial concentrations measured at five minutes in dogs exposed to the LOAEL 

concentration served as the target arterial concentrations for modeling a safe exposure for 

humans. Out of a group of dogs exposed to each chemical, the lowest measured five-minute 

value was taken as the target arterial concentration for use in modeling human exposure. The 

target arterial concentrations used were: Halon 1301, 25.7 mg/L; CF3I, 12.9 mg/L; HFC-125, 

47.8 mg/L; HFC-227ea, 26.3 mg/L; and HFC-236fa, 90.3 mg/L (Huntingdon, 1998). 

Physiologically Based Pharmacokinetic (PBPK) Model

 The human PBPK model used in this work was described by Vinegar et al. (1998) and differs 

from the more traditional PBPK model in that it includes a respiratory-tract compartment 
14 

containing a dead-space region and a pulmonary exchange area. It was used successfully to 

simulate the pharmacokinetics of halothane, isoflurane, and desflurane which are structurally 

similar to many of the chemicals being considered as halon replacements. The pulmonary 

exchange area has its own air space, tissue, and capillary subregions. Respiration is described on 

a breath-by-breath basis. This more detailed lung description was necessary to successfully 

simulate pharmacokinetic data in the 0 to 1 min range as illustrated for halothane (Vinegar et al., 

1998). Additional physiological compartments described in this model are liver, fat, lung, gut, 

slowly perfused and rapidly perfused tissues. All model compartments are perfusion limited and 

metabolism, if present, is assumed to occur in the liver. Tissue volumes, blood flows and 

ventilation rates for humans are shown in Table I. 

Chemical-Specific Model Parameters and Values 

 Blood/air partitions were measured using human blood. In some cases human tissue partition 

coefficient data were available and in others only rodent data were available. Rodent metabolic 

rate constants were available for these chemicals, but none of them had human metabolism data. 

The assumption made for this work was that rat metabolism data can be extrapolated to humans 

using allometric scaling ([body weight]0.75). Variance from this assumption does not impact the 

work here because: (1) this group of chemicals shows as a general characteristic extremely slow 

metabolism (Creech et al., 1995a,b; Vinegar et al., 1995) and (2) metabolism has not 

demonstrated an effect on these short term (five minute) simulations even when moderate levels 

are incorporated into the model. Metabolism for all chemicals was set to zero except for CF3I 

where the maximal velocity constant VMAXC = 0.375 for an allometrically scaled 1.0 kg animal 

and the Michaelis-Menten constant KM=0.1. Partition coefficients were determined using a 
15 

modification of a described tonometry method (Eger, 1987; Lerman et al., 1985; Lerman et al., 

1986) and appear in Table II. 

Monte Carlo Simulations 

 In order to consider the variability in a population Monte Carlo simulations were run with 

1000 iterations. Each iteration was sampled randomly from the designated distribution for each 

of the model constants (Tables I and II). Upper and lower bounds on normally distributed 

parameters were set at the ± 3 standard deviation levels. Monte Carlo simulations were 

performed using ACSL TOX simulation software (Pharsight Corp., Mountain View, CA) 

operating under Windows95 and WindowsNT (Microsoft Corp., Redmond, WA). 

RESULTS 

 Results of the simulations are shown graphically for each chemical (Figure 1-5). Each 

simulation line represents the mean arterial concentration plus two standard deviations for a 

1000-iteration simulation of human exposure at a given concentration. The horizontal line 

represents the target arterial concentration, i.e., the lowest dog arterial concentration measured at 

five minutes exposure to the LOAEL. At lower exposure concentrations the target arterial 

concentration is not reached in the five-minute period. As exposure concentrations are increased 

the arterial concentrations begin to approach the target arterial concentration and do so sooner at 

higher exposure concentrations. 
16 

 The same information is presented in tabular form (Table III-VII). Exposure concentration is 

presented in increments of 0.5% (0.05% for CF3I) and the time in minutes (up to 5) that a human 

can safely be exposed to that concentration is indicated. 

DISCUSSION 

 Currently, requirements for safe exposure design of Halon 1301 and potential replacement 

chemicals for use as total flooding agents in a fire-fighting scenario are specified as follows 

(U.S. EPA, 1994). 

 1. Design to NOAEL (cardiac sensitization in dog) where egress from an area cannot be 

 accomplished within one minute 

 2. Up to LOAEL if egress can occur in 30 sec to 1 min 

 3. Above the LOAEL if egress can occur in less than 30 sec and area is normally 

 unoccupied 

These specifications do not take into consideration the pharmacokinetics of the agents and the 

relationship between the exposure concentration and the internal concentration actually 

associated with a cardiac event. Examination of Tables III-VII reveals interesting relationships 

between the cardiac sensitization LOAEL and time for safe human exposure. Exposure to HFC125 can occur safely for at least five minutes at an exposure concentration of 11.5%, which is 

1.5% above the LOAEL. Similarly, exposure to HFC-227ea can occur safely for at least five 

minutes at 10.5%, which actually is the LOAEL. However, the safe five minute exposure for 

HFC-236fa occurs at 12.5% which is 2.5% below the LOAEL, for CF3I occurs at 0.3% which is 

0.1% below the LOAEL, and for Halon 1301 occurs at 5.5% which is 2.0% below the LOAEL. 
17 

 Ultimately, the duration of safe exposure must be examined in relation to the concentration of 

agent needed to extinguish a fire. A comparison can be made between the concentration for safe 

five-minute exposure and the recommended design concentration of agent. HFC-125 with an 

11.5% safe exposure concentration has a recommended design concentration of 10.0 to 11.0%. 

HFC-227ea with a 10.5% safe exposure concentration has a recommended design concentration 

of 7.0%. Thus, even though safe exposure to HFC-125 can occur above the LOAEL and to HFC227ea only at the LOAEL, the difference between the safe exposure concentration and the 

recommended design concentration is only 0.5% for HFC-125 and 3.5% for HFC-227ea. 

Interestingly, Halon 1301 with a five-minute safe exposure concentration of 5.5%, 2.0% below 

the LOAEL, has a recommended design concentration of 5.0% which is only 0.5% below the 

safe exposure concentration. Halon 1301 has a long history of safe use, which points to the 

conservative nature of the cardiac sensitization endpoint, which ultimately determines the target 

arterial concentration, which in turn is used for determining safe exposure time. 

 The cardiac sensitization endpoint occurs as a result of the exposure of a chemical sensitizing 

the heart to an epinephrine challenge. The challenge is given to the dog after five minutes of 

exposure. Therefore, the increased level of sensitivity is due to the concentration of chemical at 

the heart at five minutes. It is this level attained after five minutes of exposure that is used as the 

target for simulations of human exposure to the chemical. Whenever the simulated human 

exposure indicates that the human arterial concentration approaches that of the target level the 

assumption is made that there can then be a potential for cardiac sensitization to occur in the 

exposed human. 

 In order to account for individual variability, Monte Carlo simulations were performed. The 

mean simulated arterial concentration plus two standard deviations, which is compared with the 
18 

target arterial concentration, accounts for 97.5% of the simulated population, i.e., in 97.5% of the 

population arterial concentration would reach the target arterial concentration at the time (or 

later) where the simulation reaches the target. 

 Furthermore, the target arterial concentration used for this assessment of safe exposure is 

determined in a conservative manner. Stressed exercising dogs reached a level of circulating 

epinephrine of about 0.4 μg/L (Buhler et al., 1978; Carriere et al., 1983; Keller-Wood et al., 

1982; Young et al., 1985). The level of epinephrine used to challenge the dogs during a cardiac 

sensitization test ranges from 1.0 to 12.0 μg/kg body weight (Dodd and Vinegar, 1998). Since 

dogs have a total blood volume of about 8.2 percent body weight (Brown et al., 1997) the stated 

doses of epinephrine would result in concentrations of about 12 to 146 μg/L or 30 to 365 times 

the levels circulating under normal stressed physiological conditions. These are conservative 

estimates of the concentration that reaches the heart with an epinephrine challenge since the 

above calculation assumes that the epinephrine immediately dilutes throughout the whole blood 

volume. The actual dilution, between the site of injection into the cephalic vein and reaching the 

heart muscle through the coronary artery, takes place in about one fifth of the blood volume. This 

dilution is an estimate of the blood volume in the vasculature between the injection site and the 

arterial blood feeding the coronary arteries. It is an approximation using blood flow information 

from Leggett and Williams (1995) and Bischoff and Brown (1966). Concentrations reaching the 

heart through the coronary arteries would be five times higher than calculations above indicate 

(60 to 730 μg/L or 150 to 1825 times the circulating levels). It is recognition of the conservative 

nature of the cardiac sensitization test that allows the EPA to apply the LOAEL and NOAEL 

determined in the dog directly to humans without application of adjustment for a dog to human 

extrapolation. 
19 

 The critical issue in applying any standard for safe exposure is the relationship between the 

effective concentration of agent necessary to extinguish a fire and the concentration that poses a 

potential threat for cardiac sensitization. Where the extinguishing concentration approaches the 

cardiac sensitization concentration the agent may still be approved for use as a fire extinguishant 

but only in areas that are normally unoccupied. For candidate agents where the extinguishing 

concentration is above the cardiac sensitization concentration there is reluctance by some to risk 

using the agent because of perceived potential for accidental exposure. An additional 

consideration is that many of these agents release halogen acids upon contact with heat. The 

toxicity of these acids is of concern. Levels of release can be reduced if the fire can be put out 

quickly, which can be done if higher concentrations of extinguishing agent are used. 

 Application of the modeling technique herein described not only makes use of the 

conservative cardiac sensitization endpoint, but also uses an understanding of the 

pharmacokinetics of the chemical agents to better establish standards for safe exposure. The 

combined application of cardiac sensitization data and physiologically based modeling provides 

a quantitative approach, which can facilitate the selection and effective use of halon replacement 

candidates. 

ACKNOWLEDGMENTS 

 The animals used in this study were handled in accordance with the principles stated in the 

Guide for the Care and Use of Laboratory Animals, prepared by the Committee on Care and Use 

of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research 

Council, DHHS, National Institute of Health Publication #86-23, 1985, and the Animal Welfare 

Act of 1966, as amended. 
20 

 Support for this work was provided partially by the Department of Defense’s Next Generation 

Fire Suppression Technology Program, funded by the DoD Strategic Environmental Research 

and Development Program (SERDP) and through Department of the Air Force Contract No. 

F41624-96-C-9010. The manuscript has been reviewed by the Office of Public Affairs and 

assigned the following technical report number, AFRL-HE-WP-TR-200X-XXXX. 

 The statements and opinions expressed in this article are those of the authors and do not 

necessarily reflect the official policies of the United States Environmental Protection Agency, 

unless this is clearly specified.

REFERENCES 

Bischoff, K. B. and Brown, R. G. 1966. Drug distribution in mammals. Chemical Engineering 

Progress Symposium Series, Vol 62, No. 66, pp33-45. 

Bois, F. Y. and Paxman, D. G. 1992. An analysis of exposure rate effects for benzene using a 

physiologically based pharmacokinetic model. Regul. Toxicol. Pharmacol. 15:122-136. 

Bois, F. Y., Woodruff, T. J., and Spear, R. C. 1991. Comparison of three physiologically based 

pharmacokinetic models of benzene disposition. Toxicol. Appl. Pharmacol. 110:79-88. 

Brown, R. P., Delp, M. D., Lindstedt, S. L., Rhomberg, L. R., and Beliles, R. P. 1997. 

Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. 

Industr. Health, 13:407-484. 

Buhler, H. U., DaPrada, M., Haefely, W., and Picotti, G. B. 1978. Plasma adrenaline, 

noradrenaline and dopamine in man and different animal species. J. Physiol. 276:311-320. 
21 

Carriere, S., Demassieux, S., Cardinal, J., and LeGrimellec, C. 1983. Release of epinephrine 

during carotid artery occlusion following vagotomy in dogs. Can. J. Physiol. Pharmacol. 

61:495-501. 

Clewell, H. J. and Jarnot, B. M. 1994. Incorporation of pharmacokinetics in noncancer risk 

assessment: Example with chloropentafluorobenzene. Risk Anal. 14:265-276. 

Creech, J. R., Black, R. K., Garrity, B. L., Abbas, R., Dong, L., Williams, R. J., McDougal, J. N., 

Vinegar, A., and Jepson, G. W. 1995a. Inhalation uptake and metabolism of iodohalogenated 

compounds, CF3I, C6F13I, and C3F7I. Technical Report AL/OE-TR-1995-0089, U.S. Air 

Force, Armstrong Laboratory, Occupational and Environmental Health Directorate, 

Toxicology Division, Wright-Patterson AFB, OH, viii + 14pp. 

Creech, J. R., Black, R. K., Neurath, S. K., caracci, M. C., Williams, R. J., Jepson, G. W., and 

Vinegar, A. 1995b. Inhalation uptake and metabolism of Halon 1301 replacement candidates, 

HFC-227ea, HFC-125, and FC-218. Technical Report AL/OE-TR-1995-0022. U.S. Air 

Force, Armstrong Laboratory, Occupational and Environmental Health Directorate, 

Toxicology Division, Wright-Patterson AFB, OH, ii + 51pp. 

Cronin IV, W. J., Oswald, E. J., Shelley, M. L., Fisher, J. W., and Flemming, C. D. 1995. A 

trichloroethylene risk assessment using a Monte Carlo analysis of parameter uncertainty in 

conjunction with physiologically-based pharmacokinetic modeling. Risk Anal. 15:555-565. 

Davis, N. R. and Mapleson, W. W. 1981. Structure and quantification of a physiological model 

of the distribution of injected agents and inhaled anesthetics. Br. J. Anaesth. 53:399-405. 

Dodd, D. E. and Vinegar, A. 1998. Cardiac sensitization testing of the halon replacement 

candidates trifluoroiodomethane (CF3I) and 1,1,2,2,3,3,3-heptafluoro-1-iodopropane (C3F7I). 

Drug Chem. Toxicol. 21:137-149. 
22 

Eger, E. I. 1987. Partition coefficients of I-653 in human blood, saline, and olive oil. Anesth. 

Analg. 66:971-973. 

Farrar, D., Allen, B., Crump, K. and Shipp, A. 1989. Evaluation of uncertainty in input 

parameters to pharmacokinetic models and the resulting uncertainty in output. Toxicol. Lett. 

49:371-385. 

Hetrick, D. M., Jarabek, A. M., and Travis, C. C. 1991. Sensitivity analysis for physiologically 

based pharmacokinetic models. J. Pharmacokin. Biopharmacol. 19:1-20. 

Huntingdon Life Sciences Ltd. 1998. HFC 236fa, HFC 227ea, HFC 125 and CF3I. An 

Inhalation Study to Investigate the Blood Levels of Inhaled Halocarbons in the Beagle Dog. 

Prepared by Huntingdon Life Sciences Ltd, England. Huntingdon Report Number IFP 

001/984370. Submitted under subcontract to ICF Incorporated, Washington DC, under EPA 

Contract 68-D5-0147, Work Assignment 2-09. 

Keller-Wood, M. E., Wade, C. E., Shinsako, J., Keil, L. C., Van Loon, G. R., and Dallmann, M. 

F. 1982. Insulin-induced hypoglycemia in conscious dogs: Effect of maintaining carotid 

arterial glucose levels on the adrenocorticotropin, epinephrine and vasopressin responses. 

Endocrinology, 112:624-632. 

Leggett, R. W. and Williams, L. R. 1995. A proposed blood circulation model for reference man. 

Health Phys. 69:187-201. 

Lerman, J., Gregory, G. A., Willis, M. M., Schmidt, B. I., and Eger, E. I. 1985. Age and the 

solubility of volatile anesthetics in ovine tissues. Anesth. Analg. 64:1097-1100. 

Lerman, J., Gregory, G. A., Willis, M. M., Schmidt-Bantel, B. I., and Eger, E. I. 1986. Effect of 

age on the solubility of volatile anesthetics in human tissues. Anesth. Analg. 65:307-311. 
23 

Mullin, L. S., Reinhardt, C. F., and Hemingway, R. E. 1979. Cardiac arrhythmias and blood 

levels asociated with inhalation of Halon 1301. Amer. Ind. Hyg. Assoc. J. 40:653-658. 

Portier, C. J. and Kaplan, N. L. 1989. Variability of safe dose estimates when using complicated 

models of the carcinogenic process. Fundam. Appl. Toxicol. 13:533-544. 

Reinhardt, C. F., Azar, A., Maxfield, M. E., Smith, P. E., Jr., and Mullin, L. S. 1971. Cardiac 

arrhythmias and aerosol “sniffing”. Arch. Environ. Health, 22:265-279. 

Simon, T. W. 1997. Combining physiologically based pharmacokinetic modeling with Monte 

Carlo simulation to derive an acute inhalation guidance value for trichloroethylene. Regul. 

Toxicol. Pharmacol. 26:257-270. 

Spear, R. C., Bois, F. Y., Woodruff, T., Auslander, D., Parker, J., and Selvin, S. 1991. Modeling 

benzene pharmacokinetics across three sets of animal data: parametric sensitivity and risk 

implications Risk Anal. 11:641-654. 

Thomas, R. S., Bigelow, P. L., Keefe, T. J., and Yang, R. S. H. 1996a. Variability in biological 

exposure indices using physiologically based pharmacokinetic modeling and Monte Carlo 

simulation. Am. Indust. Hyg. Assoc. J. 57:23-32. 

Thomas, R. S., Lytle, W. E., Keefe, T. J., Constan, A. A., and Yang, R. S. H. 1996b. 

Incorporating Monte Carlo simulation into physiologically based pharmacokinetic models 

using advanced continuous simulation language (ACSL): A computational method. Fundam. 

Appl. Toxicol. 31:19-28. 

U. S. Environmental Protection Agency. 1994. “SNAP Technical Background Document: Risk 

Screen on the Use of Substitutes for Class I Ozone-depleting Substances, Fire Suppression 

and Explosion Protection (Halon Substitutes),” U. S. Environmental Protection Agency, 

Office of Air and Radiation, Stratospheric Protection Division, Washington, DC. 
24 

Vinegar, A., Buttler, G. W., Caracci, M. C., and McCafferty, J. D. 1995. Gas uptake kinetics of 

1,1,1,2,2,2-hexafluoropropane (HFC-236fa) and identification of its potential metabolites. 

Technical Report AL/OE-TR-1995-0177, U.S. Air Force, Armstrong Laboratory, 

Occupational and Environmental Health Directorate, Toxicology Division, Wright-Patterson 

AFB, OH, iv + 42pp. 

Vinegar, A. and Jepson, G. W. 1996. Cardiac sensitization thresholds of halon replacement 

chemicals predicted in humans by physiologically-based pharmacokinetic modeling Risk 

Anal. 16:571-579. 

Vinegar, A., Jepson, G. W. and Overton, J. H. 1998. PBPK modeling of short-term (0 to 5 min) 

human inhalation exposures to halogenated hydrocarbons Inhal. Toxicol. 10:411-429. 

Williams, R. J., Vinegar, A., McDougal, J. N., Jarabek, A. M., and Fisher, J. W. 1996. Rat to 

human extrapolation of HCFC-123 kinetics deduced from halothane kinetics: A corollary 

approach to physiologically based pharmacokinetic modeling. Fundam. Appl. Toxicol. 

30:55-66. 

Yang, R. S. H., El-Masri, H. A., Thomas, R. S., and Constan, A. A. 1995. The use of 

physiologically-based pharmacokinetic/pharmacodynamic dosimetry models for chemical 

mixtures. Toxicol. Lett. 82/83:497-504. 

Young, M. A., Hintze, T. H., and Vatner, S. F. 1985. Correlation between cardiac performance 

and plasma catecholamine levels in conscious dogs. Am. J. Physiol. 248:H82-H88. 
25 

Table I - Parameter Distributions for Monte Carlo Analysis 

 Parameters Means1 CV2 Upper Bound Lower 

Plasma Flows (fraction of cardiac output) 

QPC Alveolar ventilation (L/hr/kg) 17.4 0.8 QCC Cardiac output (L/hr/kg ) = QPC QFC Fat 0.029 0.30 0.042 0.0QGC Gut 0.219 0.33 0.364 0.0QLC Liver 0.089 0.32 0.147 0.0QSC Slowly perfused tissues 0.202 0.30 0.384 0.0QRC Richly perfused tissues = 1.0 – QSC – QLC- QFC- QGC 

Tissue Volumes (fraction of body weight) 

BW Body weight (kg) 70 0.26 97.3 42VFC Fat 0.215 0.24 0.409 0.0VGC Gut 0.022 0.15 0.035 0.0VLC Liver 0.027 0.25 0.043 0.0VRC Richly perfused tissues 0.041 0.30 0.066 0.0VSC Slowly perfused tissues = 0.88 – VFC – VGC – VLC – VRC 

1Mean values taken from Davis and Mapelson (1981) and Williams et al. (1996) 2Coefficients of variation taken from Thomas et al. (1996a) 
26 

Table II – Partition Coefficients (Lognormal Distribution) of Halon 1301 and Selected Replacement Agents (Geometric Mean ± GeomParameters Halon 1301 CF3I HFC-227ea HFC-125 HFC-236faPB1 0.062H ± 1.057 0.410H ± 1.118 0.033H ± 1.033 0.074H ± 1.081 0.106H ± 1.053 

PF2 0.771H ± 1.164 9.014R ± 1.145 0.347R ± 1.541 0.533R ± 1.334 0.678R ± 1.104 

PL3 0.145H ± 1.085 0.192R ± 1.380 0.031R ± 1.965 0.062R ± 1.381 0.106R ± 1.075 PR4 0.145H ± 1.085 0.192R ± 1.380 0.031R ± 1.965 0.062R ± 1.381 0.106R ± 1.075 PS5 0.159R ± 1.498 0.239R ± 1.180 0.021R ± 5.889 0.070R ± 1.230 0.091R ± 1.067 

1Blood/air2Fat/air3Liver/air4Richly perfused tissues/air5Slowly perfused tissues/air HHuman RRat 
27

Table III. Acceptable Human Exposure Times at Stated Concentrations for 

Halon 1301. 

Halon 1301 Concentration 

% v/v PPM 

Time (Minutes)* 

6.0 60,000 5.00 

6.5 65,000 1.33 

7.0 70,000 0.59 

7.5 75,000 0.42 

8.0 80,000 0.35 

 *Based on the 5-minute blood concentration of dogs exposed to Halon 1301 at 

 the LOAEL of 7.5%

Table IV. Acceptable Human Exposure Times at Stated Concentrations for 

CF3I 

CF3I concentration 

% v/v PPM 

Time (Minutes)* 

0.30 3000 5.00 

0.35 3500 4.30 

0.40 4000 0.85 

0.45 4500 0.49 

0.50 5000 0.35 

 *Based on the 5-minute blood concentration of dogs exposed to CF3I at the 

 LOAEL of 0.4% 

Table V. Acceptable Human Exposure Times at Stated Concentrations for 

HFC-125. 

HFC-125 concentration

% v/v PPM 

Time (Minutes)* 

11.5 115,000 5.00 

12.0 120,000 1.13 

12.5 125,000 0.73 

13.0 130,000 0.59 

13.5 135,000 0.50 

 *Based on the 5-minute blood concentration of dogs exposed to HFC-125 at 

 the LOAEL of 10.0%
28

Table VI. Acceptable Human Exposure Times at Stated Concentrations for 

HFC-227ea. 

HFC-227ea concentration 

% v/v PPM 

Time (Minutes)* 

10.5 105,000 5.00 

11.0 110,000 1.13 

11.5 115,000 0.60 

12.0 120,000 0.49 

 *Based on the 5-minute blood concentration of dogs exposed to HFC-227ea at 

the LOAEL of 10.5% 

Table VII. Acceptable Human Exposure Times at Stated Concentrations for 

HFC-236fa. 

HFC-236fa concentration 

% v/v PPM 

Time (Minutes)* 

12.5 125,000 5.00 

13.0 130,000 1.93 

13.5 135,000 0.99 

14.0 140,000 0.73 

14.5 145,000 0.55 

15.0 150,000 0.49 

*Based on the 5-minute blood concentration of dogs exposed to HFC-236fa at 

the LOAEL of 15.0% 
29

Figure Legends

Figure 1 – Monte Carlo simulations of arterial concentration of humans exposed to Halon 1301 

for five minutes at concentrations of 5.5, 6.0, 6.5, 7.0, 7.5, and 8.0%. The horizontal line at 

25.7 mg/L represents the lowest arterial blood concentration measured at five minutes in a 

group of six dogs exposed to Halon 1301 at the cardiac sensitization LOAEL of 7.5%. 

Figure 2 – Monte Carlo simulations of arterial concentration of humans exposed to CF3I for five 

minutes at concentrations of 0.25, 0.30, 0.35, 0.40, 0.45, and 0.50%. The horizontal line at 12.9 

mg/L represents the lowest arterial blood concentration measured at five minutes in a group of 

six dogs exposed to CF3I at the cardiac sensitization of LOAEL of 0.4%. 

Figure 3 – Monte Carlo simulations of arterial concentration of humans exposed to HFC-125 for 

five minutes at concentrations of 11.0, 11.5, 12.0, 12.5, and 13.0%. The horizontal line at 47.8 

mg/L represents the lowest arterial blood concentration measured at five minutes in a group of 

six dogs exposed to HFC-125 at the cardiac sensitization LOAEL of 10.0%. 

Figure 4 – Monte Carlo simulations of arterial concentration of humans exposed to HFC-227ea 

for five minutes at concentrations of 10.0, 10.5, 11.0, 11.5, 12.0%. The horizontal line at 26.3 

mg/L represents the lowest arterial blood concentration measured at five minutes in a group of 

six dogs exposed to HFC-227ea at the cardiac sensitization LOAEL of 10.5%. 
30

Figure 5 – Monte Carlo simulations of arterial concentration of humans exposed to HFC-236fa 

for five minutes at concentrations of 12.5, 13.0, 13.5, 14.0, 14.5, and 15.0%. The horizontal 

line at 90.37 mg/L represents the lowest arterial blood concentration measured at five minutes 

in a group of six dogs exposed to HFC-236fa at the cardiac sensitization LOAEL of 15.0%. 
31

Halon 1301

0.0 1.0 2.0 3.0 4.0 5.0

MINUTES

ARTERIAL BLOOD CONCENTRATION (mg/L)

15.0 20.0 25.0 30.0 35.0

5.5%

6.0%

6.5%

7.0%

7.5%

8.0%

EXPOSURE

CONC

0.0 1.0 2.0 3.0 4.0 5.0

MINUTES

CF3I

ARTERIAL BLOOD CONCENTRATION (mg/L)

5.0 10.0 15.0 20.0

0.25%

0.30%

0.35%

0.40%

0.45%

0.50%

EXPOSURE

CONC
32

0.0 1.0 2.0 3.0 4.0 5.0

MINUTES

ARTERIAL BLOOD CONCENTRATION (mg/L)

30.0 40.0 50.0 60.0

HFC-125

11.0%

11.5%

12.0%

12.5%

13.0%

13.5%

EXPOSURE

CONC

0.0 1.0 2.0 3.0 4.0 5.0

MINUTES

HFC-227ea

ARTERIAL BLOOD CONCENTRATION (mg/L)

15.0 20.0 25.0 30.0 35.0

10.0%

10.5%

11.0%

11.5%

12.0%

EXPOSURE

CONC
33

0.0 1.0 2.0 3.0 4.0 5.0

70.0 80.0 90.0 100.0 110.0

MINUTES

ARTERIAL BLOOD CONCENTRATION (mg/L)

12.0%

12.5%

13.0%

13.5%

14.0%

14.5%

15.0%

HFC-236fa

EXPOSURE

CONC
34

MODELING CARDIAC SENSITIZATION POTENTIAL OF 

HUMANS EXPOSED TO HALON 1301 OR HALON 1211 

ABOARD AIRCRAFT 

ALLEN VINEGAR3

, M.S., Ph.D. 

AFRL/HEST, ManTech Environmental Technology, WPAFB, OH 45433 

Short Title: HALON EXPOSURE ABOARD AIRCRAFT 

Address all correspondence to: 

Allen Vinegar 

ManTech Environmental Technology, Inc. 

P.O. Box 31009 

Dayton, OH 45437 

Phone: 937-255-5150x3145 Fax: 937-258-2197 

Email: allen.vinegar@wpafb.af.mil

 

3

 Author is currently Chief Scientist with ManTech Environmental Technology, Inc. at Wright-Patterson 

AFB, OH. 
35

Abstract 

Halon 1301 and Halon 1211 are being replaced because they contribute to the depletion 

of ozone. Many of the potential candidate chemicals for replacing them are, like them, 

halogenated hydrocarbons. These chemicals have the potential to cause cardiac 

sensitization at high enough exposure concentrations. A physiologically based 

pharmacokinetic model, which mathematically describes the uptake, distribution, 

metabolism, and elimination of chemicals, was used to relate exposure to these chemicals 

with arterial blood concentrations resulting from the exposure. This information was then 

used to evaluate the potential for the occurrence of a cardiac-sensitizing event. The model 

was used to analyze the exposures to Halon 1301 and Halon 1211 in three aircraft. Halon 

1301 exposures were shown to be safe but Halon 1211 resulted in arterial concentrations 

in exposed individuals that reached levels that could potentially cause cardiac 

sensitization. Use of the model for evaluating the risk from exposure to Halon 1301 and 

Halon 1211 is a moot point since both chemicals are being replaced. However, 

demonstration of the validity of the approach provides a tool for the evaluation of the 

health safety of replacement candidates. 

Index Terms: cardiac sensitization, halon, physiologically based pharmacokinetic model, 

fire extinguishant
36

Introduction 

Halons, used as fire extinguishants, have been banned from production because of 

international concern for the depletion of stratospheric ozone. Only existing stocks are 

available for essential application use in aircraft fire and explosion suppression systems. 

Constantly changing political pressure puts these stocks at risk for elimination, increasing 

the need to make halon alternatives available for aircraft use. Most chemicals being 

considered as replacements for Halon 1301 and 1211 are halogenated hydrocarbons 

which, as a class, are regulated by the U.S. Environmental Protection Agency (1). 

Cardiac sensitization is the acute toxic endpoint of concern. Dogs are monitored 

continually for electrocardiographic changes indicative of the appearance of a burst of 

multifocal ventricular ectopic activity or ventricular fibrillation. They are given an 

epinephrine challenge after 5 min of exposure to the test chemical. The test is performed 

at several chemical concentrations to determine a no observable adverse effect level 

(NOAEL) and a lowest observable adverse effect level (LOAEL). The LOAEL and 

NOAEL values are used directly for establishing human exposure limits because of the 

sensitive nature of the test (1). 

Recently, a mathematical tool was developed which allows the quantitative evaluation of 

short-term exposure to halogenated hydrocarbons (2). This tool is a physiologically based 

pharmacokinetic (PBPK) model, which can relate chemical exposure to concentrations in 

the body. It has been proposed that the model be used to relate external exposure of halon 

replacement chemicals to arterial blood concentration. Arterial blood concentration can 

then be compared with a target arterial blood concentration associated with cardiac 
37

sensitization. The methodology for doing this has been proposed (3) and described in 

detail (4). 

The PBPK model can be used both retrospectively to evaluate previous actual exposure 

scenarios and prospectively to evaluate potential exposure scenarios. An example of a 

retrospective evaluation was given in Vinegar et al. (2) where they evaluated an 

accidental exposure to Halon 1211 that had occurred during an Israeli military exercise 

(5). In this instance, model predictions were consistent with the outcome where the 

gunner, having only brief exposure, successfully escaped without incident but the driver, 

with prolonged exposure, reached levels adequate for cardiac sensitization. The driver, in 

fact, was observed to be in ventricular fibrillation, never regained consciousness and died 

as a result of the incident. A prospective application of the model was demonstrated by 

Vinegar et al. (6). In order to evaluate the potential hazard to ground crews of an 

accidental release of CF3I a discharge test was conducted on an F-15 jet to record CF3I 

concentration time histories at various locations near the aircraft. These exposure data 

were used with the PBPK model to simulate the potential blood levels of workers at 

various locations around the aircraft during the release. The blood levels were compared 

to the target arterial blood concentration associated with cardiac sensitization. Results 

showed that at some locations the target was not reached but at the open nacelle the blood 

concentrations could potentially reach double the target. This information was put in 

perspective with a further retrospective simulation of individuals who had actually 

inhaled CF3I and whose blood concentrations were simulated and estimated to be 100 

times the target. These individuals experienced no apparent effect of their exposures. 

Further prospective application of the model was demonstrated in Vinegar et al. (4). Here 
38

a method was demonstrated for establishing safe duration for exposure to potential halon 

replacements at different flooding concentrations. 

An issue of health concern is that of the intentional use of fire extinguishers in aircraft 

cabins with passengers aboard. No data were available for any of the potential halon 

replacements. However, there have been several published reports on measurements 

taken in aircraft cabins during the release of Halon 1301 and Halon 1211. These data 

were used with the PBPK model to see if any of the described scenarios could put 

passengers or crew at potential risk for cardiac sensitization. Results of these simulations 

are reported herein. 

Materials and Methods 

Three publications were found that presented data on releases of Halon 1211 and/or 

Halon 1301 in aircraft. The first study (7) used a fleet configured Navy E-2B “Hawkeye” 

airplane. Concentrations of Halon 1301 were measured at head level in areas occupied by 

flight crewmembers, and in airplane locations where fire hazard potential posed the 

greatest threat. Halon 1301 was monitored using a Statham Laboratories Model GA-2A 

gas recorder and accessories. 

The second study (8) used a Cessna Model C-421B, a small pressurized aircraft. Halon 

1211 and Halon 1301 were measured using factory field modified Beckman Model 865 

infrared gas analyzers. Measurements were made at three locations: 

1. Test area – Actual fire extinguisher discharge location. 
39

2. Knee area – 20 inches above the floor at the area of discharge. Discharge area for 

pilot’s and copilot’s seat tests was at knee level where the seat cushion meets the seat 

back. 

3. Nose area – 37 inches above the floor at the area of discharge. 

The last study (9) used a Cessna Model 210C, a small non-pressurized aircraft. Halon 

1211 and Halon 1301 were measured using modified Beckman Model 865 infrared gas 

analyzers. Measurements were made at the point of release and at two other selected sites 

during each test. 

In all three publications there are diagrams showing the specific locations monitored. The 

data were presented in graphic form. Results reaching the highest peak exposure 

concentrations were used from each paper. The data were digitized and converted to 

ASCII so that they could be used with the PBPK model. Exposure scenarios selected 

were used to simulate the arterial concentration using the model described by Vinegar et 

al. (2). Arterial concentrations were compared with target arterial concentrations for 

cardiac sensitization (4). 

Results 

Representative results for the Navy E-2B are shown in Figures 1 and 2. A ground test is 

illustrated in Figure 1. Concentrations of Halon 1301 measured at four locations are 

shown in the left-hand column. Simulated arterial concentrations for each of the four 
40

locations are shown in the right hand column. The straight line shown at 25.7 mg/L for 

each of the arterial simulations represents the target concentration for cardiac 

sensitization. None of the simulated concentrations reached the target. An example of a 

flight test is shown in Figure 2. Under these conditions at floor level in the equipment 

area the concentrations of Halon 1301 in arterial blood exceeded the target concentration 

at about 40 seconds into the exposure and remained above the target for the duration of 

the measurements. Arterial concentration simulations remained below target at the other 

measured sites. 

Results for representative releases aboard the Cessna C-421B are shown in Figures 3 to 6. 

Halon 1301 releases at the last vent before the left side door (Figure 3) or at the last vent 

on the right side of the cabin (Figure 4) resulted in simulated arterial concentrations well 

below the target concentration. Both releases of Halon 1211 resulted in simulated arterial 

concentrations that surpassed the target concentration of 21.0 mg/L (Figures 5 and 6). 

The target was exceeded at both sites of release. The release at the copilot’s seat (Figure 

5) had measurements at nose level, which exceeded the target after about 45 seconds of 

exposure. Release at the cabin side of grill under the copilot’s seat resulted in simulated 

arterial concentration at the knee area exceeding the target after about 16 seconds and 

peaking at more than three times the target at about 26 seconds (Figure 6). However, nose 

area concentrations remained below the target. 

Halon 1301 arterial concentrations remained below the target concentration for releases, 

in the Cessna 210C, directed to the copilot’s door with overhead vents closed (Figure 7) 

and directed to fuel and hydraulic selector valves with overhead vents open (Figure 8). 
41

Halon 1211 arterial concentrations exceeded the target level at all measured locations 

when the extinguisher was directed under the instrument panel on the pilot’s side with 

overhead vents open (Figure 9) or closed (Figure 10). 
42

SECONDS

Figure 1 - Halon 1301 - Ground Test (equipment cooling System ON) for Navy E-2b. Concentrations of

Halon 1301 measured at four locations are shown in the left hand column. Simulated arterial

concentrations for each of the four locations are shown in the right hand column. The straight line shown

at 25.7 mg/L for each of the arterial simulations represents the target concentration for cardiac sensitization.

0 60 120 180 240 300 0 60 120 180 240 300

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 6 12 18 24 30

0 8 16 24 32 40

0 60 120 180 240 300 0 60 120 180 240 300

Personnel Area

0 60 120 180 240 300 0 60 120 180 240 300

0 6 12 18 24 30

0 8 16 24 32 40

Head Level

Equipment Area

0 60 120 180 240 300 0 60 120 180 240 300

0 6 12 18 24 300 8 16 24 32 40

Floor Level

Equipment Area

0 6 12 18 24 30

0 8 16 24 32 40

Aft Equipment

Area
43

Figure 2 - Halon 1301 - Flight Test (Nozzle Jets Mixing Agent) for Navy E-2B. Concentrations of Halon

1301 measured at four locations are shown in the left hand column. Simulated arterial concentrations

for each of the four locations are shown in the right hand column. The straight line shown at 25.7 mg/L

for each of the arterial simulations represents the target concentration for cardiac sensitization.

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 60 120 180 240 300 0 60 120 180 240 300

0 6 12 18 24 30

0 8 16 24 32 40

Personnel Area

0 60 120 180 240 300 0 60 120 180 240 300

0 6 12 18 24 30

0 8 16 24 32 40

Head Level

Equipment Area

0 60 120 180 240 300 0 60 120 180 240 300

0 6 12 18 24 300 8 16 24 32 40

Floor Level

Equipment Area

0 60 120 180 240 300 0 60 120 180 240 300

0 6 12 18 24 30

0 8 16 24 32 40

Aft Equipment

Area
44

Figure 3 - Halon 1301 - Concentrations Cabin Area Last Vent Before Door Left Side for

Cessna C-421B. Concentrations of Halon 1301 measured at three locations are shown in the

left hand column. Simulated arterial concentrations for each of the three locations are shown

in the right hand column. The straight line shown at 25.7 mg/L for each of the arterial

simulations represents the target concentration for cardiac sensitization.

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 8 16 24 32 40 0 8 16 24 32 40 0 8 16 24 32 40

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Test Area

Knee Area

Nose Area
45

Figure 4 - Halon 1301 - Concentrations Cabin Area Last Vent Right Side for Cessna C-421B.

Concentrations of Halon 1301 measured at three locations are shown in the left hand column.

Simulated arterial concentrations for each of the three locations are shown in the right hand

column. The straight line shown at 25.7 mg/L for each of the arterial simulations represents

the target concentration for cardiac sensitization.

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 8 16 24 32 40 0 8 16 24 32 40 0 8 16 24 32 40

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Test Area

Knee Area

Nose Area
46

Figure 5 - Halon 1211 - Concentrations Copilot’s Seat for Cessna C-421B. Concentrations

of Halon 1211 measured at three locations are shown in the left hand column. Simulated

arterial concentrations for each of the three locations are shown in the right hand column.

The straight line shown at 21.0 mg/L for each of the arterial simulations represents the target

concentration for cardiac sensitization.

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Test Area

Knee Area

Nose Area
47

Figure 6 - Halon 1211 - Concentrations Cabin Side Of Grill Under Copilot’s Seat for Cessna

C-421B. Concentrations of Halon 1211 measured at three locations are shown in the left hand

column. Simulated arterial concentrations for each of the three locations are shown in

the right hand column. The straight line shown at 21.0 mg/L for each of the arterial simulations

represents the target concentration for cardiac sensitization.

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

0 18 36 54 72 90 0 18 36 54 72 90

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Test Area

Knee Area

Nose Area
48

Figure 7 - Halon 1301 - 3-lb Extinguisher Directed To Copilot’s Door - Overhead Vents

Closed for Cessna 210C. Concentrations of Halon 1301 measured at three locations are shown

in the left hand column. Simulated arterial concentrations for each of the three locations are

shown in the right hand column. The straight line shown at 25.7 mg/L for each of the arterial

simulations represents the target concentration for cardiac sensitization.

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 8 16 24 32 40 0 8 16 24 32 40 0 8 16 24 32 40

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Pilot-copilot

Belt Level

Pilot’s Nose

Level

Under Instrument

Panel Pilot’s Side
49

Figure 8 - Halon 1301 - 3-lb Extinguisher Directed To Fuel And Hydraulic Selector

Valves - Overhead Vents Open for Cessna 210C. Concentrations of Halon 1301 measured at

three locations are shown in the left hand column. Simulated arterial concentrations for each

of the three locations are shown in the right hand column. The straight line shown at 25.7 mg/L

for each of the arterial simulations represents the target concentration for cardiac sensitization.

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 8 16 24 32 40 0 8 16 24 32 40 0 8 16 24 32 40

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Pilot-copilot

Belt Level

Pilot’s Nose

Level

Fuel And

Hydraulic

Selector Valve
50

Figure 9 - Halon 1211 - 2.5-lb Extinguisher Directed Under Instrument Panel Pilot’s Side -

Overhead Vents Open for Cessna 210C. Concentrations of Halon 1211 measured at three locations

are shown in the left hand column. Simulated arterial concentrations for each of the three

locations are shown in the right hand column. The straight line shown at 21.0 mg/L for each of

the arterial simulations represents the target concentration for cardiac sensitization.

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Pilot-copilot

Belt Level

Pilot’s Nose

Level

Under Instrument

Panel Pilot’s Side
51

Figure 10 - Halon 1211 - 2.5-lb Extinguisher Directed Under Instrument Panel Pilot’s

Side - Overhead Vents Closed for Cessna 210C. Concentrations of Halon 1211 measured at

three locations are shown in the left hand column. Simulated arterial concentrations for each of

the three locations are shown in the right hand column. The straight line shown at 21.0 mg/L for

each of the arterial simulations represents the target concentration for cardiac sensitization.

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100

SECONDS

CONCENTRATION IN AIR (%)

ARTERIAL CONCENTRATION (MG/L)

0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100

0 3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15

Pilot-copilot

Belt Level

Pilot’s Nose

Level

Under Instrument

Panel Pilot’s Side
52

Discussion 

The use of Halon 1301 for several decades has occurred with an excellent safety record. 

Retrospective modeling of scenarios such as those illustrated above show that generally 

under normal use there has been little to no opportunity for the occurrence of exposure 

situations where individuals have been put at potential risk of having blood levels of 

Halon 1301 ever reach a target concentration that might predispose for the onset of a 

cardiac sensitization response. Halon 1211 when used as a streaming agent under open 

conditions likewise has posed little risk. However, when used under more confined 

situations the potential for cardiac sensitization exists. Several scenarios illustrated above 

showed situations where arterial concentrations of Halon 1211 exceeded the target 

associated with a potential for cardiac sensitization. The report of an incident by Lerman 

et al. (5) (see introduction) demonstrates that the risk is real if Halon 1211 is used under 

confined situations where the exposure concentration can get high enough to result in 

highly elevated blood concentrations. 

The discussion with reference to Halons 1301 and 1211 is perhaps a moot point with both 

of them being replaced with other agents. However, the use of PBPK modeling to 

evaluate exposure scenarios with replacement agents should be considered. Prospective 

modeling of potential scenarios can forewarn against situations such as that reported by 

Lerman et al. (5). 

Acknowledgments 
53

Support for this work was provided partially by the Department of Defense’s Next 

Generation Fire Suppression Technology Program, funded by the DoD Strategic 

Environmental Research and Development Program (SERDP); through an Interagency 

Agreement between the U.S. EPA and the Department of the Air Force; and through 

Department of the Air Force Contract No. F41624-96-C-9010. The manuscript has been 

reviewed by the Office of Public Affairs and assigned the following technical report 

number, AFRL-HE-WP-TR-200X-XXXX. 

Literature Cited 

1. “SNAP Technical Background Document: Risk Screen on the Use of Substitutes for 

class I Ozone-Depleting substances, Fire Suppression and Explosion Protection (Halon 

Substitutes),” Federal Register 59:13044(1994). 

2. Vinegar, A., G.W. Jepson, and J.H. Overton. 1998. PBPK modeling of short-term (0 to 

5 min) human inhalation exposures to halogenated hydrocarbons. Inhal. Toxicol. 10:411-

429. 

3. Vinegar, A. and G.W. Jepson. 1996. Cardiac sensitization thresholds of halon 

replacement chemicals predicted in humans by physiologically based pharmacokinetic 

modeling. Risk Anal. 16:571-579. 
54

4. Vinegar, A., G.W. Jepson, M. Cisneros, R. Rubenstein, and W. J. Brock. 200X. Setting 

safe acute exposure limits for halon replacement chemicals using physiologically-based 

pharmacokinetic modeling. Inhal. Toxicol. (in press). 

5. Lerman, Y., E. Winkler, M.S. Tirosh, Y. Danon, and S. Almog. 1991. Fatal accidental 

inhalation of bromochlorodifluoromethane (Halon 1211). Hum. Exp. Toxicol. 10:125-

128. 

6. Vinegar, A., G.W. Jepson, S.J. Hammann, G. Harper, D.S. Dierdorf, and J.H. Overton. 

1999. Simulated blood levels of CF3I in personnel exposed during its release from an F15 jet engine nacelle and during intentional inhalation. Amer. Indust. Hyg. Assoc. J. 

60:403-408. 

7. Smith, D.G. and D.J. Harris. 1973. Human exposure to Halon 1301 (CBrF3) during 

simulated aircraft cabin fires. Aerospace Med. 44:198-201. 

8. Abramowitz, A., W. Neese, and G. Slusher. 1990. Smoke and extinguisher agent 

dissipation in a small pressurized fuselage. US Dept. of Transportation, Federal Aviation 

Administration. DOT/FAA/CT-89/31. 

9. Slusher, G.R., J. Wright, and J. Demaree. 1986. Halon extinguisher agent behavior in a 

ventilated small aircraft. US Dept. of Transportation, Federal Aviation Administration 

DOT/FAA/CT-86/5. 
55

Physiologically Based Pharmacokinetic 

Model for Simulating Breath-By-Breath 

Inhalation
56

PROGRAM: PHYSIOLOGICAL PHARMACOKINETIC MODEL 

!Ventilation described on a breath-by-breath basis 

!---------------------------------------------------------------------- 

!AS=INTEG(RAS,0.) Amount slowly perfused tissue (mg) 

!AR=INTEG(RAR,0.) Amount rapidly perfused tissue (mg) 

!AF=INTEG(RAF,0.) Amount in fat (mg) 

!AG=INTEG(RAG,0.) Amount in gut (mg) 

!AM=INTEG(RAM,0.) Amount amount metabolized in liver (mg) 

!AL=INTEG(RAL,0.) Amount in liver (mg) 

!CVGDD=INTEG(RCVGDD,0.0) concentration (mg/L) in distal deadspace 

!CVGDP=INTEG(RCVGDP,0.0) concentration (mg/L) in proximal deadspace 

!AI=INTEG(RAI,0.) Amount inhaled (mg) 

!AX=INTEG(RAX,0.) Amount exhaled (mg) 

!AP=INTEG(RAP,0.0) AMOUNT IN PULMONARY REGION (mg) 

!---------------------------------------------------------------------- 

INTEGER CTABLE, VTABLE, ICRP, BREATH, INHALE, VGDCAL,IGEVGD,IHALT $'FLAGS' 

TABLE VENTT,1,19/0.,.0016667,.0033333,.005,.0066667,.0083333,... 

.0125,.0166667,.025,.0333333,.05,.0833333,.125,.1666667,... 

.2083333,.25,.3333333,.4166667,.5,... 

5.42,5.42,5.42,5.42,5.42,5.42,5.42,5.42,5.42,5.42,5.42,5.21,... 

5.19,5.19,5.33,5.53,5.27,5.58,5.58/ 

TABLE CONCT,1,19/0.,.0016667,.0033333,.005,.0066667,.0083333,... 

.0125,.0166667,.025,.0333333,.05,.0833333,.125,.1666667,... 

.2083333,.25,.3333333,.4166667,.5,... 

2025.,2025.,2025.,2025.,2025.,2025.,2025.,2025.,2025.,2025.,2025.,... 

1996.,1966.,2000.,2035.,2014.,2051.,2056.,2034./ 

INITIAL 

!**Miscellaneous** 

LOGICAL GENDER, MALE 

GENDER=.TRUE. $ 'Male=.T., Female=.F.' 

MALE = GENDER 

!**Timing commands** 

CONSTANT TSTOPS =300 !LENGTH OF EXPERIMENT (SECS) 

 TSTOP =TSTOPS/3600 

CONSTANT TCHNG =40 !Length of inhalation exposure (hr) 

!**Physiological Parameters** 

CONSTANT VGDCAL =1 !>=1: calculate VGD. <1: use input value 

of VGD 

CONSTANT CTABLE =-1 !1 !Switch for using the table 

CONCT 

CONSTANT VTABLE =-1 !1 !Switch for using the table, 

VENTT 

CONSTANT ICRP =0 !SWITCH FOR METHOD OF CALCULATING 

VT & F 

CONSTANT KAP =0 !PUL. REGION GAS PHASE RATE CONSTANT 

CONSTANT KS =10000 !Suppression rate constant (mg/hr) 

CONSTANT BW =70 !Body weight (kg) {or L where 1 L/kg} 
57

CONSTANT H =1.8 !Height (m) 

CONSTANT A =21 !Age (yr) 

CONSTANT QPC =17.4 !L/(hr*kg) 

 QP =QPC*BW**0.74 !L/hr 

 QPM =QP/60 !L/min 

 VENTLM =QPM/0.70 !L/min=70% OF QPM 

CONSTANT QLC =0.0885 !Proportion cardiac output to liver 

CONSTANT QGC =0.2192 !Proportion cardiac output to gut 

CONSTANT QFC =0.0288 !Proportion cardiac output to fat 

CONSTANT QSC =0.2019 !Proportion cardiac output to slow 

CONSTANT QRC =0.4616 !Proportion card output to rapid 

 QRCC =QRC 

CONSTANT VLC =0.027 !Liver volume (L/L BW) 

CONSTANT VGC =0.022 !Gut volume (L/L BW) 

CONSTANT VFC =0.215 !Body fat volume (L/L BW) 

CONSTANT VRC =0.041 !Rapid volume (L/L BW) 

CONSTANT VSC =0.575 !Slow volume (L/L BW) 

!**Toxicant** 

CONSTANT CONC =105000 !Inhaled concentration (ppm) 

CONSTANT MW =168.02 !Molecular weight (g/mol) 

CONSTANT VMAXC =0.0 !Michaelis-Menten Vmax (mg/hr/kg BW) 

CONSTANT KM =1 !Michaelis-Menten Km (mg/L) 

CONSTANT KFC =0. !First order metab. rate constant (1/hr/kg BW) 

CONSTANT PLA =0.038 !Liver/air partition coefficient 

CONSTANT PGA =0.056 !Gut/air partition coefficient 

CONSTANT PFA =0.745 !Fat/air partition coefficient 

CONSTANT PSA =0.074 !Slowly perfused tissues/air part. coefficient 

CONSTANT PRA =0.038 !Richly perfused tissues/air part. coefficient 

CONSTANT PB =0.033 !Blood/air partition coefficient 

 PL =PLA/PB !Liver/blood partition coefficient 

 PG =PGA/PB !Gut/blood partition coefficient 

 PF =PFA/PB !Fat/blood partition coefficient 

 PS =PSA/PB !Slowly perfused tissues/blood part. coefficient 

 PR =PRA/PB !Richly perfused tissues/blood part. coefficient 

CONSTANT PI =3.1415927 

!CONSTANT VT =0.5 !TIDAL VOLUME (L) 

CONSTANT F =900 !BREATHING FREQUENCY /HR 

CONSTANT VGP =3. !PULMONARY REGION GAS VOLUME 

CONSTANT VGD =0.2 !DEAD SPACE GAS VOLUME 

CONSTANT VPR =1. !VENTILATION PERFUSION RATIO 

CONSTANT VCAPP =0.169 !VOL OF PUL CAPILLARIES 

CONSTANT VTP =0.270 !VOL OF PUL TISS (AIR-BLOOD BARRIER) 

!**Scaled and other derived parameters** 

FRC =0.65*(2.34*H+.009*A-1.09) !FUNCTIONAL RESIDUAL CAPACITY (L) 

IF(.NOT. MALE) FRC=.65*(2.24*H+.001*A-1.00) 

IF(VGDCAL .LE. 0) GOTO 20 

 VGD =0.002*bw !VGD from Lerou et al.(1991)' 

 20..CONTINUE 

 VGP =FRC-VGD 

 VL =VLC*BW !Volume liver (L) 
58

 VG =VGC*BW !Volume gut (L) 

 VF =VFC*BW !Volume fat (L) 

 VR =VRC*BW !Volume rapid (L) 

 VS =VSC*BW !Volume slow (L) 

 VMAX =VMAXC*BW**0.75 !Vmax for toxicant (mg/hr) 

 KF =KFC/BW**0.25 !First-order metabolism of toxicant (1/hr) 

!**VARIABLE INITILIZATION** 

!**Inhalation exposure** 

IF(CTABLE .GT. 0.5) ... 

 CONC=CONCT(T) !INHALED CONC DERIVED FROM 

TABLE (PPM) 

 CIZONE =RSW((T.LT.TCHNG),1.,0.) !Exposure switch, 0 or 1 

 !CI =CONC*MW/24450.*CIZONE !Concentration inhaled (mg/L) 

 CI =RSW((T.LT.TCHNG),CONC*MW/24450.,.0000000000000001) 

!**Activity** 

IF(VTABLE .GT. 0.5) ... 

 VENTLM=VENTT(T) !VENTILATION DERIVED FROM 

TABLE (L/MIN) 

 VT =(VENTLM*60.)/F !TIDAL VOLUME DERIVED FROM 

VDOTE & FREQ 

IF( ICRP .LT. 0.5) GO TO 100 

 VT =3.050*(1.0-EXP(-0.023*VENTLM))+0.166 

 !(L),VT EQ. FOR ADULT FROM HOFMANN ET 

AL.(89); 

 !BASE ON ICRP # 23(75). 

 F =VENTLM*60/VT !BREATHS/HR 

100..CONTINUE 

 VTA =VT-VGD !MAX VOL OF FRESH AIR 

PENETRATION INTO PUL REGION.' 

 VDOTA =F*VTA !ALVEOLAR VENTILATION (L/HR) 

 VDOTE =VT*F !TOTAL VENTILATION (L/HR) 

 QCI =VDOTA/VPR !CARDIAC OUTPUT=ALVEOLAR 

VENTILATION/V:P RATIO 

!IF(VPR .GT. 1E6) QCI =0.0 !SET VPR > 1E6 FOR NO BODY UPTAKE 

 QL =QLC*QCI !Blood flow to liver (L/hr) 

 QG =QGC*QCI !Blood flow to gut (L/hr) 

 QF =QFC*QCI !Blood flow to fat (L/hr) 

 QS =QSC*QCI !Blood flow to slow (L/hr) 

 QR =QRCC*QCI !Blood flow to rapid (L/hr) 

 QC =QL+QG+QF+QS+QR 

 PERIOD =1.0/F 

 !MAXT(4) =PERIOD/(2*NMAXT) 

 HALFP =PERIOD/2 

 OMEGA =2.*PI*F 

 CINT = PERIOD/(2*NCIPHB) 

 CI =CONC*MW/24450. 

!CVGDD = 0.0 $ !CVGDP = 0.0 $ !CGP = 0.0 

IHALF = 0 $ INHALE = 1 $ UPTAKE = 0 

!AG=0 $ !AF=0 $ !AL=0 $ !AS=0 $ !AR=0 $ !AD=0 $ !AP=0 

!AM=0 $ !AX=0 $ !AI=0 $ !VOLEX=0 $ !BREATH=0 

!AI=0 $ !AX=0 $ !DOSEXL=0.0 $ !DOSEPB=0.0 $ !AMRPB=0.0 
59

!IGEVGD=0.0 $ !RATEI=0.0 $ !RATEX=0.0 $ !RATEP=0 $ !CXMIX=0 

!AXL=0.0 $ !AXPB=0.0 $ !AMRPH=0 $ !AVGDD=0 $ !AVGDP=0 $ !CX=0 

!CXALV=0 $ !CXON2=0 $ !DOSEX=0 

massba=0 $ minute=0 $ rmasba=0 $ rmass=0 $ second=0 

secxxx=0 $ tbody=0 $ ti=0 $ tmass=0 $ txxx=0 

xx=0 $ xxx=0 

SCHEDULE IN1 .AT. 0.0 !NEW 

END !End of initial 

!---------------------------------------------------------------------------------- 

DYNAMIC 

CONSTANT NMAXT =1 !MIN NO OF INTEG STEPS PER PERIOD 

CONSTANT NCIPHB =1 !# OF COMMUNICATION INTERVALS 

PER HALF BREATH 

ALGORITHM IALG =2 

NSTEPS NSTP =1000000 

MAXTERVAL MAXT =1.0E+33 

MINTERVAL MINT =1.0E-33 

CINTERVAL CINT =2.22E-5 

DISCRETE IN1 !PROCEDURAL 

PROCEDURAL 

 CALL LOGD(.TRUE.) 

 XX = AI - AX !Total amount retained 

 DOSEPB = XX - DOSEXL !Dose per breatH 

 DOSEXL = XX !Previous amount retained 

 AXPB = AX - AXL !Amount exhaled per breath 

 AXL = AX !Previous amount exhaled 

!Inhalation exposure**' 

'********** Activity ********' 

IF(VTABLE .GT. 0.5) ... 

VENTLM=VENTT(T) !VENTILATION DERIVED FROM TABLE 

(L/MIN) 

 VT =(VENTLM*60.)/F !TIDAL VOLUME DERIVED FROM VDOTE & 

FREQ 

IF( ICRP .LT. 0.5) GO TO 200 

! 'VT EQ. FOR ADULT FROM HOFMANN ET AL.(89); BASE ON ICRP # 23(75).' 

 VT = 3.050*(1.0 - EXP(-0.023*VENTLM)) + .166 $ '(L)' 

 F =VENTLM*60/VT !BREATHS/HR 

200..CONTINUE 

 PERIOD =1.0/F 

 !!MAXT(4) =PERIOD/(2*NMAXT) 

 HALFP =PERIOD/2 

 OMEGA =2.*PI*F 

 CINT =PERIOD/(2*NCIPHB) 

 VDOTPI =PI*VDOTE !PI*TOTAL VENTILATION 

(L/HR) 
60

 VTHALF =VT/2.0 

 BREATH =BREATH+1 !Counting breaths 

 IHALF =IHALF+1 !Counting half breaths 

 TI =HALFP*IHALF !Time at given half breath 

SCHEDULE EX1 .AT. TI !Schedule exhale at end of 

inhale 

 XXX =(1/OMEGA)*ACOS(1.-VGD/VTHALF) !Time within breath that inh 

vol=ds 

 TXXX =T+XXX !Absol time at which inh 

vol=dead space 

 SECXXX =TXXX*3600 

SCHEDULE GEVGD .AT. TXXX !Schedule integration restart at 

TXXX 

 IGEVGD =-1 !Flag to change pulmonary rate 

equation 

 INHALE =1 !Inhale state 

 CVGDP =CI !Proximal deadspace conc=inhaled conc 

CALL RSTART(DEV1, 1.E-7) !Integration restart 

CALL LOGD(.TRUE.) 

END !END PROCEDURAL 

END !END DISCRETE IN1 

DISCRETE GEVGD 

PROCEDURAL 

IGEVGD = 1 

CALL RSTART(DEV1, 1E-7) 

CALL LOGD(.TRUE.) 

END 

END 

DISCRETE EX1 $ PROCEDURAL 

 CALL LOGD(.TRUE.) 

 IHALF = IHALF + 1 $'Counting half breaths' 

 TI = HALFP*IHALF $'Time at given half breath' 

 SCHEDULE IN1 .AT. TI $'Schedule inhale at end of exhale' 

 INHALE = -1 $'Exhale state' 

 CVGDD = CGP $'Distal deadspace conc = pulmonary conc' 

 CALL RSTART(DEV1, 1.E-7) $'Integration restart' 

 CALL LOGD(.TRUE.) 

END $'END PROCEDURAL' 

END $'END DISCRETE EX1' 

'*********************************** DERIVATIVE ********************' 

DERIVATIVE DEV1 $ PROCEDURAL $ '*********************************' 

IF(CTABLE .GT. 0.5) ... 

 CONC=CONCT(T) $'INHALED CONCENTRATION DERIVED FROM TABLE (PPM)' 

CIZONE=RSW((T.LT.TCHNG),1.,0.) $ 'Exposure switch, 0 or 1' 

'CI=CONC*MW/24450.*CIZONE' $ 'Concentration inhaled (mg/L)' 

CI=RSW((T.LT.TCHNG),CONC*MW/24450.,.0000000000000001) 
61

SINX=SIN(OMEGA*T) 

SINHX=SIN((OMEGA*T)/2) 

FLOW=VDOTPI*ABS(SINX) 

DELVOL=VTHALF*(1.0-COS(OMEGA*T)) 

VOLP=VGP+DELVOL 

'**TOXICANT PHARMACOKINETICS**' 

'**Toxicant in blood**' 

CA=AP/(VOLP/PB+VTP*PR+VCAPP) $ 'Arterial conc. (mg/L)' 

ACA=INTEG (CA, 0.0) !AUCCA OF CA 

CTP=CA*PR 

CGP=CA/PB 

'**Toxicant in slowly perfused tissues**' 

CS=AS/VS $ 'Concentration (mg/L)' 

CVS=CS/PS $ 'Concentration in venous outflow (mg/L)' 

RAS=QS*(CA-CVS) $ 'Rate of change (mg/hr)' 

AS=INTEG(RAS,0.) $ 'Amount (mg)' 

'**Toxicant in rapidly perfused tissues**' 

CR=AR/VR $ 'Concentration (mg/L)' 

CVR=CR/PR $ 'Concentration in venous outflow (mg/L)' 

RAR=QR*(CA-CVR) $ 'Rate of change (mg/hr)' 

AR=INTEG(RAR,0.) $ 'Amount (mg)' 

'**Toxicant in fat**' 

CF=AF/VF $ 'Concentration (mg/L)' 

CVF=CF/PF $ 'Concentration in venous outflow (mg/L)' 

RAF=QF*(CA-CVF) $ 'Rate of change (mg/hr)' 

AF=INTEG(RAF,0.) $ 'Amount (mg)' 

'**Toxicant in gut**' 

CVG=AG/(VG*PG) 

CG=AG/VG 

RAG=QG*(CA-CVG) 

AG=INTEG(RAG,0.) 

'**Toxicant in liver**' 

CL=AL/VL $ 'Concentration (mg/L)' 

CVL=AL/(VL*PL) $ 'Concentration in venous outflow (mg/L)' 

RAM=(VMAX*CVL)/(KM+CVL*(1+CVL/KS)) $ 'Rate (mg/hr)' $'metabolism' 

AM=INTEG(RAM,0.) $ 'Amount (mg)' 

RAL=QL*(CA-CVL)+QG*(CVG-CVL)-RAM $ 'Rate of change (mg/hr)' 

AL=INTEG(RAL,0.) $ 'Amount (mg)' 

CV = 0.0 

IF(QC .GT. 0.0) CV=(QF*CVF+(QL+QG)*CVL+QS*CVS+QR*CVR)/QC $ ' (mg/L)' 

VOLEX=VT-DELVOL 

'BEGINDS' 

IF(INHALE .LT. 1) GOTO EXHALE 

 'INHALE PHASE: SINX >= 0.0 ' 
62

 CMOUTH=CI $ 'Conc at mouth equals inhaled conc' 

 RAI=FLOW*CI $ 'Rate of inhalation (mg/hr)' 

 RAX = 0.0 $ 'RATE OF EXHALATION' 

 'proximal compartment' 

 VGDP = MIN(DELVOL,VGD) 

 RATEI = FLOW/(VGDP + (1E-4)*VGD) 

 RCVGDP = FLOW*(CI - CVGDP)/(VGDP+(1E-4)*VGD) 

 'distal compartment' 

 VGDD = VGD - VGDP 

 RCVGDD = 0.0 

 IF(IGEVGD .LT. 0.0) RATEP = FLOW*CVGDD 

 IF(IGEVGD .GT. 0.0) RATEP = FLOW*CVGDP 

 GOTO ENDDS 

EXHALE..CONTINUE 

 RATEP=-FLOW*CGP 

 IF(VOLEX .LT. VGD) CMOUTH=CVGDP $'Conc at mouth equals DS conc' 

 IF(VOLEX .GE. VGD) CMOUTH=CVGDD $'Conc at mouth equals PUL conc' 

 RAX=FLOW*CMOUTH $ 'Rate of exhalation (mg/hr)' 

 RAI = 0.0 $ 'RATE OF INHALATION' 

 'distal compartment' 

 VGDD= MIN(VOLEX, VGD) 

 RATEX = FLOW/(VGDD + (1E-4)*VGD) 

 RCVGDD=FLOW*(CGP-CVGDD)/(VGDD+(1E-4)*VGD) 

 'proximal compartment' 

 VGDP = VGD - VGDD 

 RCVGDP = 0.0 

ENDDS..CONTINUE 

CVGDD=INTEG(RCVGDD,0.0) $'concentration (mg/L) in distal deadspace' 

CVGDP=INTEG(RCVGDP,0.0) $'concentration (mg/L) in proximal deadspace' 

AI=INTEG(RAI,0.) $ 'Amount inhaled (mg)' 

AX=INTEG(RAX,0.) $ 'Amount exhaled (mg)' 

RAP=RATEP+QC*(CV-CA) - KAP*CGP $ 'TOTAL RATE OF CHANGE OF AMOUNT IN' 

 'PULMONARY REGION' 

AP=INTEG(RAP,0.0) $ 'AMOUNT IN PULMONARY REGION' 

END $ END $ 'END PROCEDURAL & End of derivative ******************' 

'**Toxicant mass balance**' 

AVGDP = CVGDP*VGDP 

AVGDD = CVGDD*VGDD $ 'NEW !!!!!!!!!!!!!!!!!!!!!' 

AD=AVGDD+AVGDP $ 'AMOUNT IN DEAD SPACE' 

TMASS=AG+AF+AL+AS+AR+AD+AP+AM+AX $ 'Total dose (mg)' 

DOSEX=AI-AX $ 'Net amount absorbed (mg)' 

TBODY=AG+AF+AL+AS+AR+AD+AP $ 'Total in tissues (mg)' 

MASSBA=AI-TMASS 

RMASS=AG+AF+AL+AS+AR+AD+AP+AM $ 'TOTAL RETAINED MASS (MG)' 

RMASBA=DOSEX-RMASS $ 'MASS BALLANCE' 

'AVERAGE MASS RETAINED PER BREATH:' 
63

IF(BREATH .GT. 0) AMRPB = DOSEX/BREATH $'AVERAGE MASS RETAINED/BREATH' 

AMRPH = F*AMRPB $ 'AVERAGE MASS RETAINED/HOUR' 

IF(AI .GT. 0.0) UPTAKE = DOSEX/AI $ 'AVERAGE FRACTIONAL UPTAKE' 

'**Toxicant exhaled**' 

IF(BREATH .GT. 0.0) ... 

CXMIX = (AXPB/VT)*24450/MW $ 'Mixed exhaled conc. (ppm)' 

CX=CA/PB $ 'Exhaled alveolar conc. (mg/L)' 

CXALV=CX*24450./MW $ 'Exhaled alveolar conc. (ppm)' 

CONSTANT CXEND=5.39106 

CXON2=RSW((T.LT.TCHNG),(CX/CI),CX/CXEND) 

MINUTE=T*60 

SECOND = 3600*T 

'**Condition for termination of run**' 

TERMT(T.GE.TSTOP) 

'----------------------------------------------------------------------' 

END $ 'End of dynamic' 

'----------------------------------------------------------------------' 

END $ 'End of program' 
64

APPENDIX: 

Setup File for Performing MonteCarlo Simulation Using ACSL-Tox 

Software
65

% FILE: setup.m 

% Defines functions for implmenting a Monte-Carlo simulation 

% ---------------------------------------------------------------- 

% NORMAL - Returns a normally distributed random variable with 

% mean mu and standard deviation sigma. 

% ---------------------------------------------------------------- 

function v=normal(mu, sigma) 

 v = mu + sigma*randn(1,1) ; 

end 

% ---------------------------------------------------------------- 

% NORMBND - Returns a truncated normal distribution with 

% mean mu, standard deviation sigma, upper and 

% lower bound 

% ---------------------------------------------------------------- 

function v=normbnd(mu, sigma, lower, upper) 

 if(lower >= upper) 

 v = NaN; 

 return; 

 end 

 while ( 1 ) 

 v = normal(mu, sigma) ; 

 if (v >= lower & v <= upper) 

 break; 

 end 

 end 

end 

% ---------------------------------------------------------------- 

% LOGNORMAL - Returns a lognormally distributed random variable 

% with geometric mean mu and geometric standard deviation 

% sigma 

% ---------------------------------------------------------------- 

function v=lognormal(mu, sigma) 

 r1 = rand(1,1) ; % uniform distributtion 

 r2 = rand(1,1) ; % uniform distributtion 

 

 v = exp(log(mu) + log(sigma)*sin(pi()*2*r1)*sqrt(-2*log(r2))) ; 

end 

% ---------------------------------------------------------------- 

% PMINMAX - plot mean, min and max of a matrix 

% ---------------------------------------------------------------- 

function pminmax(x,y) 

 bar = mean(y')'; 

 maximum = max(y')'; 

 minimum = min(y')'; 

 curve = [minimum bar maximum]; 

 plot(x, curve); 

end 

% End of file
66

APPENDIX: 

Sample M File for Conducting Monte Carlo 

Simulation for Halon 1301. Must Be Used in 

Conjunction With The Setup File
67

% File: halon.m 

% Date: 14 Aug 98 

% This will run a Monte Carlo simuation 

!! prepare minute, ca 

!! set mw=148.91 

!! set wesitg=.f. 

!! set vmaxc=0, km=10000, kfc=0 

sprintf('CINT=%g. Are you sure?', CINT) 

pause 

% Empty the bucket into which I will be saving output 

caBucket=[]; 

caHist =[]; 

% Run it one hundred times 

%figure 

 for run=1:numRun 

 run 

% Vary the body weight 

% Fraction of total body volume allocated to various compartments 

%Means from Dr. Vinegar 

%Coefficient of Variation from Thomas (Am. Ind. Hyg. Ass. J.) 

BW =normbnd(70, 9.1, 42.7, 97.3); 

VFC =normbnd(0.215, 0.0645, 0.0215, 0.4085); 

%FOR VGC CV IS ASSUMED TO BE =20% 

VGC =normbnd(0.022, 0.0044, 0.0088, 0.0352); 

VLC =normbnd(0.027, 0.0054, 0.0108, 0.0432); 

VRC =normbnd(0.041, 0.0082, 0.0164, 0.0656); 

VSC =0.88 - VFC - VGC - VLC - VRC; 

VGP =normal(3.0, 0.60); 

VGD =normal(0.2, 0.04); 

VTP =normal(0.270, 0.054); 

VCAPP =normal(0.169, 0.0338); 

%F =normal(900, 0.8); 

% Fraction of total blood volume going to various compartments 

%Means from Dr. Vinegar 

%Coefficient of Variation from Thomas (Am. Ind. Hyg. Ass. J.) 

QPC =lognormal(17.4, 0.8); 

QSC =normbnd(0.2019, 0.06057, 0.02019, 0.38361); 

QLC =normbnd(0.0885, 0.01947, 0.03009, 0.14691); 

QFC =normbnd(0.0288, 0.00432, 0.01584, 0.04176); 

QGC =normbnd(0.2192, 0.048224, 0.074528, 0.363872); 
68

QRC =1.0 - QSC - QLC - QFC - QGC; 

% Partition coefficients 

PLA = lognormal(0.144594, 1.085094); 

PGA = lognormal(0.150, 1.25); 

PFA = lognormal(0.771412, 1.163943); 

PSA = lognormal(0.159411, 1.497855); 

PRA = lognormal(0.144594, 1.085094); 

PB = lognormal(0.061841, 1.057053); 

 % Run the simulation 

 !! start 

%plot (_minute, caBucket); 

 % Put the final in the bucket by appending it to the 

 % end. 

 caBucket= [ caBucket ; CA ] ; 

 % Put the history into the final column of this bigger 

 % bucket, caHist. 

 caHist = [ caHist _ca ]; 

end 

% Finished 

%figure 

% hAxis=axes() 

% set (hAxis, @xLim=[0 5]) 

% set (hAxis, @yLim=[0 40]) 

% xlabel ('MINUTE'), ylabel ('ARTERIAL CONC (MG/L)') ; 

% title ('HALON1301 7.5% LOAEL') ; 

%plot(_minute, caHist, 'k') ; 

% Calculate the mean, standard deviation, max, and min of ca 

meanHist=mean(caHist')' ; 

maxHist=max(caHist')' ; 

minHist=min(caHist')' ; 

stdHist=std(caHist')' ; 

ca2sg=[meanHist + 2*stdHist meanHist meanHist - 2*stdHist] 

% Open a new plot window 

%figure 

% hAxis=axes() 

% set (hAxis, @xLim=[0 5]) 

% set (hAxis, @yLim=[0 40]) 
69

% xlabel ('MINUTE'), ylabel ('ARTERIAL CONC (MG/L)') ; 

% title ('HALON1301 7.5% LOAEL') ; 

%plot(_minute, meanHist, 'k') ; 

%h=line(_minute, maxHist) ; 

%set(h,@color='k') 

%h=line(_minute, minHist); 

%set(h,@color='k'); 

% Open a new plot window 

figure 

 hAxis=axes() 

 set (hAxis, @xLim=[0 5]) 

 set (hAxis, @yLim=[0 30]) 

 xlabel ('MINUTE'), ylabel ('ARTERIAL CONC (MG/L)') ; 

 title ('HALON1301 7.5% LOAEL') ; 

plot(_minute, ca2sg, 'k') ; 

% Save the mean data into a Excel file 

%mydata=[_minute meanHist ] ; 

%save mydata @file=mydata.csv @format=ascii @separator=comma 

% end of file