Maldtlun Toxicology. 12 7S1-763. 21xx) 

OR95-R378/00$1200+ 00 

I 

Most proposed replacements for Halon 130 1 as a hre suppressant are halogenated hydrocarbons The acute toxic endpoint of concern for there agents is cardiac sensibzalion An 

approach is described that links the cardiac endpoint ds assc~sed in dogs to a target arterial 

concentrabon in humans Linkage was made using a physiologically based pharmacokinetic (PBPK) model Monte Carlo simulabons, which account for population vaiiability, 

were used to establish safe exposure times at drfferent exposure concentrations for Halon 

1 KIT lbromotiifluoromethane), CF,l (trifluoroiodomethane), HFC- 125 lpentafluoroethane), HFC-227ea (I, 1,1,2,3,3,j-heptd~uoro~r~ne), and HFC-236fa (I, I, I, 3,3,3- 

hexafluoi opropane) Application of the modeling technique described here not only 

1 

1 

~ 

SETTING SAFE ACUTE EXPOSURE LIMITS FOR HALON 

REPLACEMENT CHEMICALS USING PHYSIOLOGICALLY 

BASED PHARMACOKINETIC MODELING 

Allen Vinegar, Gary W. jepson 

AFRIJHEST, ManTech Environmental Technology, Wright-Patterson 

Air Force Base, Ohio, USA 

Mark Cisneros 

Great Lakes Chemical Corporation, West Lafeyette, Indiana, USA 

Reva Rubenstein 

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

William J. Brock 

Haskell Laboratory for Toxicology and Industrial Medicine, DuPont 

Company, Newark, Delaware, USA 

Received 29 November 1999; sent for revision 3 lanuary 2000, revision returned 14 January 

This article is not subject to U.S. copyright laws 

Support for this work was provided partially by the Department of Defense (DoD) 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 F41624-96-C-9010. 

lhe manuscript has been reviewed by the Office of Public Affairs and assigned the following technical 

report number: AFRL-HEST-WP-JA-1999-003 1 

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

reflect the official policies of the U S. Environmental Protection Agency, unless this is clearly specified. 

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

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

Animafs 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, a5 amended. 

Current address for Gary Jepson is Haskell Laboratory for '1oxicology and Industrial Medicine, 

DuPont Company, Newark, DE, USA Current address for William 1. Brock is Unilever Research-U.S., 

Edgewater, NJ, USA, 

Address correspondence to Allen Vinegar, ManTech Environmental Technology, Inc , PO Box 

31009, Dayqon, OH 4.5437, USA. E-mail: allen.vinegar@he wpafb af mil 

2000, accepted 18 January 2000. 

751 
752 A. VINEGAR ET AL. 

makes use or the consemdri\ e c aidiai sensitization ciidpoint, but ah uses an iinderstanding of the pharmacokinetics of the chemical agents to better establish standards 

for sdfe expoturf IhP combined ,?pp/ication of cardiac seii5ibzdii0ii ddtd and physiologically based modeling provides a quantitative approach, which can facilitate the 

selection and effective use oihalvn replacement candidates 

Many, if not most, of the proposed replacements for Halon 1301 (bromotrifluoromethane) 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 et al., 1971; Mullin et al., 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 (1 996) 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 lowest-observed-adverse-effect level (LOAEL) 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 5 min 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 5 

min 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. 

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 at., 1991; Bois & Paxman, 1992; Clewell & Jarnot, 

1994; Cronin et al., 1995; Farrar et al., 1989, Hetrick et al., 1991; Portier 

& Kaplan, 1989; Simon, 1997; Spear et al., 1991; Thomas et al., 1996a, 

1996b; Yang et al., 1995). However, none of these studies involved predicting short-term (0 to 5 min) effects. This article 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) 
SAFE FXPOSlJRE LIMITS FOR HALON REPLACEMENTS 753 

and four potential replacement chemicals: CF,I rtrifluoroiodoniethane), 

HFC-125 (pentafluoroethane), HFC-227ea (1,l ,I ,2,3,3,3-heptafluoropropane), and HFC-236fa (1 ,I ,1,3,3,3-hexafluoropropane). 

METHODS 

Target Arterial Concentrations of Chemical in Blood 

Arterial concentrations measured at 5 min 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 5-min 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; CFJ, 12.9 mg/L; HFC-125, 

47.8 mg/L; HFC-227ea, 26.3 mg/L; and HFC-23fifat 90.3 mg/L (Huntingdon 

Life Sciences, 1998). 

Physiologically Based Pharmacokinetic Model 

The human PBPK model used in this work was described by Vinegar 

et at. (1998) and differs from the more traditional PBPK model in that it 

includes a respiratory-tract compartment containing a deadspace 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 airspace, 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, and slowly perfused and 

rapidly perfused tissues. All model compartments arc 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 1. 

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]' 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 at., 19954 1995b; Vinegar et al., 1995) and (2) metabolism has 

not demonstrated an effect on these short-term (5-min) simulations even 
754 A. VINEGAR ET AI. 

rABLE I. Parameter distributions for Monte Carlo dndlysis 

Upper Lower 

Parameters Medns CV bound bound Distribution 

P1dsm.s ilows ifraction of cardiac output) 

C-ardtac output WhAg ) = QPC 

..... ....... 

QPC Alveolar ventilation IUh/kg\ 174 08 Lognormal 

QCC 

QFC Fat 0 079 0.30 0 042 ll.016 Normal 

QCC Gut 0219 0 33 0364 0 075 Normal 

QLC Liver 0 089 0.32 0.147 0 030 Kormal 

QSC Slowly perfused tissues 0.202 030 0384 0.020 Normal 

QRC Richly perfuwd tissues = 

1 0 - QSC-QLC - QFC - QGC 

Tissue volumes riraction of body weight, 

61%' Body weight (kgr 70 026 97.3 42 7 Normal 

VFC Fat 0213 0 24 0.109 0.022 Normal 

VGC Gut 0022 015 0035 00088 Normal 

VLC Liver 0027 025 0043 0011 Normal 

VKC Richly perius~d tissues 0041 030 0066 0016 Normdl 

VSC Slowly perfused tissues = 

0.88 - VFC - VCC - VLC - VRC 

Note Mean values taken from Davis and Mapelson (1981) and Williams et at (1996). Coefficients 

of variation taken irom Thomas et al (1 996a) 

when moderate levels are incorporated into the model. Metabolism for all 

chemicals was set to zero except for CF,I, where the maximal velocity 

constant q,,,,,,, = 0.375 for an allometrically scaled 1 .O-kg animal and the 

Michaelis-Menten constant KM = 0.1. Partition coefficients were determined using a modification of a described tonometry method (Egcr, 1987; 

Lerman et at., 1985, 1986) and appear in Table 2. 

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 1 and 2). Upper and lower bounds on normally distributed paraTABLE 2. Partition tocfficrents (lognormal distribution) of Halon 1301 and selected ieplacement agents 

(geometric mean + geomrtric standard deviation) 

Parameters Halon 1301 CFJ HFC-227ea HFC-125 H FC-2 3 6fa 

PB OO6ZH*1.057 0410"fl 118 0033"f1.033 O074"+ 1.081 0.106H*1 053 

PF 0.771"* 1 164 9011R& 1 145 0.347'Ri 1 S41 0.533'f 1.334 O.h78'+ 1 104 

PL 0.145" + 1.085 0.192'f 1 380 0.031R f 1 965 0 062'f 1.381 0 106E i: 1.075 

PR 0 145" f 1.085 0.192'% 1 380 0.031' i 1 965 0.0€~2~ f 1 381 0 10GR i 1.075 

PS 0 l59'f 1 498 0.73gR f 1.180 0 021'~ 5.889 0.070K i 1.230 0 091* f 1 067 

....... .... ..... 

~~~ ~ 

Note PH, bloocllair, PF, ht/dir; PL, fiver/air; PR, richly perfused tissuedair; PS, slowly perfused tissuedair. Superscripts: t 1, human, R, rat 
SAFF EXPOSlJRE LIMITS FOR HALON REPLACEMENTS 755 

meters were set at the k2 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., Kedmond, WA). 

RESULTS 

Results of the simulations are shown graphically for each chemical 

(Figures 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, that is, the lowest dog arterial concentration measured at 5 min of exposure to the LOAEL. At lower exposure 

concentrations the target arterial concentration is not reached in the 5- 

min period. As exposure concentrations are increased, the arterial concentrations begin to approach the target arterial concentration and do so 

sooner at higher exposure concentrations. 

The same information is presented in tabula1 form (Tables 3-7). Ex- posure concentration is presented in increments of 0.5% (O.OS% for CF,I), 

and the time in minutes (up to 5) that a human can safely be exposed to 

that concentration is indicated. 

EXPOSURE 

8.0% 

7.5% 

7.0% 

65% 

6.0% 

5.5% 

0.0 1 .o 2.0 3.0 4.0 5.0 

MINUTES 

FIGURE 1. Munte Carlo simulations of arterial concentration of humans exposed to Halon 1301 for 

5 rnin at concentrations of 5.5, 6.0, 6 5, 7.0, 7.5, and 8.0%. The horizontal line at 25.7 mgil represents the lowest arterial blood concentration measured at 5 min in a groiip of b dogs exposed to 

Halon 1701 at the cardiac sensitization LOAEL of 7.5%. 

! 
A. VINEGAK ET AL. 

0.50% 

0.45% 

0.40% 

035% 

0.30% 

0.25% 

0.0 1 .o 2.0 3.0 4.0 5.0 

MINUTES 

FIGURE 2. Monte Carlo simulations of arterial roncentration of humans exposed to CF,I for 5 min 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 S min in a group of 6 dog5 exposed to CFJ 

at the caidiac sensitization of LOAM of 0 4%. 

DISCUSSION 

Currently, requirements for safe exposure design of Halon 1301 and 

potential replacement chemicals for use as total flooding agents in a firefighting scenario are specified as follows (U.S. EPA, 1994). 

1. Design to NOAEL (cardiac sensitization in dog) where egress from an 

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

3. Above the LOAF1 if egress can occur in less than 30 s and area is norarea cannot be accomplished within 1 min. 

mally 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 3-7 reveals interesting relationships between the cardiac sensitization LOAEL and time for safe human exposure. Exposure to HFC-125 

can occur safely for at least 5 min 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 5 min at 10.So/o, which actually is the LOAEL. How- 
SAFE EXPOSURE LIMITS FOR HALON REPLACEMENTS 757 

ever, the safe 5-min exposure for HFC-236fa occurs at 12.5'!/0, which is 2.5% 

below the LOAEL; for CF,I occiirs at 0.3O/& which is 0.1 Yo below the LOAEL; 

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

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 5-min 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 1 1 .O%. 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 HFC-227ea 

only at the LOAFI., the difference between the safe exposure concentration and the recommended design concentration is only 0.5% for HFC125 and 3.5% for HFC-227ea. Interestingly, Halon 1301 with a 5-min 

safe exposure concentration of 5.5%, 2.0°/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. 

EXPOGURE 

coI\'c 

13.5% 

13.0% 

12.5% 

12.0% 

11.5Yo 

11.0% 

0.0 1.0 2.0 3.0 4.0 5.0 

MINUTES 

FIGURE 3. Monte Carlo simulations of arterial concentration of humans exposed to HFC-125 for 5 

rnin at Concentrations of 11 0, 11.5, 12 0, 12.5, and 13 0, and 1?.5% The horizontal line at 47.8 

mg/L represents the lowest arterial blood concentration measured at 5 min in a group of 6 dogs 

exposed to HFC-125 at the cardiac Sensitization I.OAEL of 10 0% 
758 A. VINEGAR ET AL. 

z EXPOSURE 9 COhC 

z 11 .O% 

8% 10.0% 

- - 12.0% 

+ - 11.5yo 

U - 10.5% z 2- - 

HFC-227ea 

0.0 1 .o 2.0 3.0 4.0 5.0 

MINUTES 

FIGURE 4. Montc Carlo simulations of aiterial concentrdtion oi humans exposed to HFC327ea for 5 

min at concentrations of 10 0, 10 5, 11 0, 11 5, and 12.0"in. The horizontal fine at 26 3 mg/L represents the lowest arterial blood concentration rncasured at 5 min in a group of 6 dogs exposed to 

HFC-227ea at the cardiac sensitization LOAEI. of 10 5% 

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

a chemical sensitizing the heart to an epinephrine challenge. lie challenge 

is given to the dog after 5 min of exposure. Therefore, the increased level of 

sensitivity is due to the concentration of chemical at the heart at 5 min. It is 

this level attained after 5 min 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 [or individual variability, Monte Carlo simulations 

were performed. The mean simulated arterial concentration plus two 

standard deviations, which is compared with the target arterial concentration, accounts for 97.5% of the simulated population; that is, 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 

pg/L (Buhler et al., 1978; Carriere et al., 1983; Keller-Wood et al., 1982; 

Young et at., 1985). The level of epinephrine used to challenge the dogs 
SAFF EXPOSURE LIMITS FOR HALON REPLACEMENTS 759 

3 

b E v 

5 rz 

w 

V 

2 

0 

9 

w 

EXPOSIRE 

- CONC 

15.0% 

' 14.5% 

14.0% 

13.5% 

13.0% 

12.5?'0 

12.0% 

0.0 1 .o 2.0 3.0 4.0 5.0 

MINUTES 

FIGURE 5. Monte Carlo simulations ot arterial concentration oi humans exposed lo HFC-236fa for 5 

min at concentrations oi 12, 12 5. 13 0, 13 5, 14 0, 14.5, and 15.00%. The horizontal ltne at 90.37 

mg/L reprezents the lowest arterial blood concentration measured at 5 min in a group of b dogs 

exposed to HFC-236ra at the cardiac seiisitization L04EL of 15 U'h. 

during a cardiac sensitization test ranges from 1 .O to 12.0 pg/kg body weight 

(Dodd & Vinegar, 1998). Since dogs have a total blood volume of about 

8.2% of body weight (Brown et al., 1997) the stated doses of epinephrine 

would result in concentrations of about 12 to 146 pg/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 preceding calculation assumes thal the 

TABLE 3. Acceptable human exposure times nt stated conccntrations for Halon 1301 

tlalon 1301 concentration 

"10 VIV PPm Time (rniny 

60 60,000 5 00 

65 65,000 I .33 

70 70,000 0 59 

75 75,000 0.42 

8.0 80,000 0 35 ~~ 

"Based on the 5-min blood concentiation of dogs exposed to 

Halon 1301 at the LOAFL of 7 5%. 
760 A. VINEGAR ET AL. 

TABLt 4. Acceptable human exposure limes at stated (oncentratiom foi CF,I 

CF,I Concentration .._--.____ 

Time (min)’ Yo VI\. PPm ~~ __ ~ 

0 70 7000 5 00 

0 35 3500 4 30 

0 40 4000 0 85 

0 45 4500 0 49 

0.50 5000 0 35 

aBa5ed on the 5-min blood concentration of dogs exposed to 

CF,I at the LOAEL of 0 4% 

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 voiume in the vasculature between the injection site and the arterial blood 

feeding the coronary arteries. it is an approximation using blood-flow information from Lcggett and Williams (1995) and Bischoff and Brown (1966). 

Concentrations reaching the heart through the coronary arteries would be 

five times higher than the preceding calculations indicate (60 to 730 pg/L or 

I50 to 1825 times the circulating levels). It is recognition of the conservative 

nature of the cardiac sensitization test that allows the U.S. Environmental 

Protection Agency (EPA) to apply the LOAEL and NOAEL determined in the 

dog directly to humans without application of adjustment for a dog-tohuman extrapolation. 

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 

TABLE 5. Acceptable human exposure times at stated concentrations b HFC-125 

HFC-125 concentration 

~~~ 

11.5 11 5,000 5.00 

12 0 120,000 1.13 

12.5 123,000 0 73 

13.0 130,000 0 59 

13 5 13 5.000 0.50 

“Based on the 5-min blood concentration of dogs exposed tu 

HFC-125 at the LOAEL of 10 0% 
SAFE EXPOSURE LIMITS FOR HALON REPLACEMENTS 761 

TABLE 6. Acceptable human exposure tirncs at stated concentidtions for HFC-227ea 

HFC-227ea concentration 

~ 

10 4 105,OoO 5 00 

11 0 ll0,oOO 113 

11.5 1 15,000 0.60 

12 0 120,000 0.43 

"Based on the 5-min blood concentration of dogs ~X~JOS~CJ to 

HFC-227ea at the LOAEL of 10 5%. 

sensitization. Where the extinguishing concentration approaches the cardiac sensitization concentration, thc agent may stili 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 accidcntal 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 sensitizatian data and physiologically based modeling provides a quantitative approach, which can facilitate the selection and effective use of 

halon replacement candidates. 

TABLE 7. Acceptable human exposure trmw at slated conccntration5 for HfC-23hfa 

12 5 125,000 5.00 

13.0 130,OOO 1.93 

13 5 135,Ooo 0 99 

14.0 140,000 0.7 I 

14 S 145,000 0 55 

15 0 150,000 0 49 

'Based on the 5-min blood concentration of dogs exposed to 

HFC-236fa at the LOAEL of 15.0%. 
762 A. VINEGAR LT AL. 

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