T0XICOU)GICAL SCIWCES 60.20-27 (2001) 

Copynght 8 2001 by the Society of Toxicology 

PBPK Modeling of Canine Inhalation Exposures 

to Halogenated Hydrocarbons 

A. Vinegar' 

ManTech Envrmnmenlal Tcc)i~iohgy, Inc , P 0. Box 31009. Lhyton. Ohro 45437 

Received September 20.2000, accepted November 16.2000 

Human exposure guidelines for halogenated hydrocarbons 

(halons) and halon replacement chemicals have been established 

using doeresponse data obtained from canine cardiac sensitization studies. In order to provide a tool for decision makers and 

regulators tasked with setting guidelines- for egress from exposure 

to halon replacement chemicals, a quantitative approach, using a 

PhYsiolosi~Y - P . etic madel, was established 

that allowed expasures to be d in terms of the chemical 

concentrations in blood during the exposure. This model, which 

includes a respiratory tract compartment containing a dead-space 

region, a pulmonary exchange area, and a breath-by-breath description of respiratory tract uptake, allows successful simulation 

of exhaled breath concentrations of humans during the first 

minute of exposure to the anesthetics halothane, isdhuane, and 

desflurane. In the current study, the human model was modified 

with canine parameters and validated with data OMained from 

dog studies with halothane, isoflurane, desfiurane, and CFC-11. 

With consideration of appropriate values for ventilation and cardiac output, the model successfully simulated data collected under 

a variety of expoawe scenarios. The raninexnodel can be used for 

simulating blood concentrations associated with the potential for 

cardiac sensitization. These target blood concentrations can then 

be used with the human mode4 for establishing safe human em 

sure duration. Development of the canine model stresses the need 

for appropriate data collection for model validation. 

Key Words: PBPK model; canine; halogenated hydrocarbons; 

halothane; isoflurane; deSilWw CFC-11. 

Replacement of ozone-depleting substances (ODs) has required quantitative toxicological evaluation of halon replacement chemicals. Historically. these volatile halogenenated organic compounds have been regulated on the basis of cardiac 

sensitization tests conducted in dogs (U.S. EPA, 1994). The 

dogs are challenged simultaneously with epinephrine and the 

test chcmical of interest, while cardiac electrical activity is 

monitored for cardiac arrhythmia. The test is conducted at 

increasing concentrations of the test chcmical in order to determine a no-observed-adverse-effect level (NOAEL) and a 

lowest-observed-adverse-effect level (LOAEL). 

' To whom comspondence should be addrcsseci at P.O. Box 1878. West 

Chenter. OH 45071. E-ma& avinegarQcinci rrcorn. 

Determining suitable permissible human exposure limits for 

halon replacement chemicals necessitates attention to both the 

level and duration of exposure. A procedure employing physiologically based pharmacokinetic (PBPK) modeling to establish egress times for humans in a halon replacement chemical 

environment waq proposed by Vinegar and Jepsan (1996). 

Implementation of the procedure required modification of the 

respiratory tract (RT) compartment description commonly uscd 

in PBPK models (Vinegar et ai., 1998). Usually, the PBPK RT 

compartment uses a steady-state approximation that results in 

an initial, unrealistically high arterial blood concentration. The 

steady-state approximation is suitable for describing inhalation 

exposures lasting from minutes to hours but is not able to 

describe the first second to minute of an exposure. Using the 

model with the modified RT, Vinegar et af. (2000) described a 

procedure for setting safe acute exposure limits for halon 

replacement chemicals. They linked the cardiac sensitization 

endpoint, after 5 niin of exposure to the LOAEL concentration, 

to the associated arterial concentration. This arterial concentration measured in dogs was then used as the target concentration for simulated human exposures. For a given exposure 

concentration, the time until a human reached the target arterial 

concentration was considered safe from the potential for cardiac sensitization. However, pharmacokinetic studies in dogs 

are expensive. If a canine PBPK model could be used to predict 

the &rial concentration, the major experimental cost would 

be for the determination of partition coefficients. 

The purpose of this study was to mdi and validate an 

existing PBPK model for use with dogs. The model was 

originally developed to predict blood and exhaled breath chemical concentrations in humans during inhalation exposures of 

less than 5 minutes duration and includes a breath-by-breath 

description of inhalation in humans (Vinegar et ul., 2000). 

Several data sets were found in the literature, containing pharmacokinetic data in dogs that were exposed by inhalation to the 

volatile anesthetics halothane (2-bromo-2chloro- 1,1, I-trifluoroethane), isoflurane (2-chloro-2-[difluoromethoxy]-1 ,I ,I -trifluoroethane), and desflurane (2-fluoro-2-[difluromethoxy~- 

1 , 1 ,1-trifluoroethane) and to the chlorofluorocarbon CFC- I 1 

(trichlorofluoromethane). An additional data set was found 

where CFC-11 was administered by intravenous injection. 

20 
MODELING OF CANINE INHALATION EXPOSURES 21 

TABLE 1 

Chemical-Specific Model Parameters and Values 

Parameter __- ._-_l-._l-_ 

ivlolecular wt @/mol) 

Vmaxc, max metabohc rate (mmg) 

Km, affimty constant (mgfl) 

Blood air partition coefficient 

Livecair pamuon coefficient 

Gut:= parhuon coefficient 

Fat:dr plutrhon coefficient 

Rapidly perfused.au parhhon coefficient 

Slowly perfud.air partiuon coefficient 

Chemical 

Halothane Isoflurane ~ 

197.39 

7.4' 

0 1" 

3 51d 

6 ad 

4 23d 

155.0d 

6 64' 

5 49 

184 5 

074" 

0.lh 

1.3' 

4.2' 

3.8' 

75 0' 

4.2' 

34' 

Desflurane CFC-I1 

168 0 

.0074' 

0.1' 

0.42' 

0.588' 

0.36," 

12 d 

0.588' 

0.966 

137.36 

0.0 

0.0 

I .5' 

1.648 

1.22' 

45 6' 

1.64' 

0.81' 

Williams era/., 1996. 

%oladay et al , 1975 

'Sutton et d.. 1991. 

'Steward et al., 1975. 

Thomas. 1975. 

'Chang and Chiou, 1976. 

%gm, 1990. 

These data were used to validate the use of the modified model 

for the dog. We discuss the importance of data quality and 

appropriateness of parameter values. 

MATERIALS AND METHODS 

Data uscd for model development and validatroo come from several sources 

Azar et ul. (1973) performed mhalahon exposures of dogs to CFC-11 Chiou 

and Niau (1973) administad CFC-11 by inmvenous injechon. Isoflurane 

inhalation exposuns were adnunistercd by Thomas (1975), Frei et 01. (1988). 

and Wmlm (personal communication) The latter 2 investigations also presented data for deshane and halothane. Hughes et al. (1980) pmented 

addihonal halothane dak Further details of the exposures follow. 

Azar et al (1973) exposed awake male beagles (11-14 kg) to CFC-11 via 

a facemask Aaerial and venous concentramm were presented from 10-mm 

exposures to 0.1%. 0.5%. and 1.0%. 

Chiou and Nazi (1973) gave a 3-min intravenous tnfrlsion of 28 mg of 

CFC-11 dissolved m 36 ml normal saline to a 45-kg mongrel dog. Venous 

conccnblltions wcre prescntwl over a 4-h puiod 

Thomas (1975) exposed ancsthehzcd. &idy ventdated beagles to 

isofliiraoc through a tracheal cannula. The cannula was connwtrd to a nombreathing valve in a closed loop system that contained a CO, scrubber and an 

inflow of 0,. Data presented for an 8.5-kg male and a 7.0-kg female dog 

included total venhlation. rcspmtory rate. mhaled concentrahon, exhaled 

Eoncentrahon. and arterial concenhatlon 

Frei et al. (1988) exposed anesthetmd. artificially ventilated mongrel dogs 

(24-39 kg) separately to isoflurane and halothane through a tracheal cannula. 

The ancsthehcs were delivered using a feedbeck-contmlled delivery system 

that maincaned a constant end alveolar concentration of agent Bdmg rate 

maintam arterial carbon dioxide at 40 mm Hg Data presented mcluded 

inspired and endexpimi concenWon, artenal and nuxed venous concentration, and cdac output 

Hughes et al. (I 980) exposcd anesthehzed, adicially ventilated greyhounds 

(20-30 kg) to halothane through a tracheal cannula. Data pnsented included 

artcnal concentration and cardiac output 

Wllhelm (personal comrpunicatton) exposed anesthetked, artificially ventiwas malntmed at 12 brraths per rmn Wlth tidal volume bung vaned to 

lated male beagles (12.8 kg mean weight) for 4 h separately. to 1766 

isoflurane and 8.94% desflme through a tracheal cannula. Exhaled conccntrauon data were presented. 

A breath-by-breath PBPK model (Vmegm et al., 1998) that was uscd to 

simulate short-term (0 to 5 mm) human mnhalat~on exposurc to vanous halogenated hydrocarbons was rnod~fied to mclude appmpnate parameter values 

for dogs The respuatory tract descnptim differs from usual PBPK models m 

that it accounts expltcitly for dead space (upper nspuatory tract and tracheobronchial region) and pulmonary region vohuncs, inhalationcxhalation, the 

time delay fw air and gases to travel through the dead-.We volume and the 

pulmonary region, the absowm of the ded gas by pulmonary regon 

tissues, and the exchange of the gas with blood. These enhancements allowed 

the succescful simulation of the first several breaths of exposure. which was not 

possible with the tra&bd PBPK dwmphon of lung uptake. 

Partlhon coefficients wm obtarncd from the literature and are listed with 

atat~ons in Table 1. The metabok constants for halothane were taken from 

Wdliams et al. (1996). Vmaxc (maximum metabolic rate) for isoflurane was 

set to one hundredth and for desflurane to one thousandth of that for halothane 

(Holaday. 1977, Holaday et al., 1975, Smon et d, 1991). 

Anatormc volumes and physiological parameters used III the model are 

sbown III Table 2. VentiIatlw parameters were scaled to body weight, except 

when actual values were provided. 

All simulations were perfotmed using ACSL Tox V1.l (Pharsight Corp.. 

Mountah View, CA) on a Pentium Ill FC with a 550-MH;c CPU. Adequacy of 

model fit was judged by visual mpechon of smulahon and data. 

RESULTS 

Azar et al., 1973. Arterial and venous concentrations during 10-min exposure and 20-min postexposure to 0.1 %, 0.58, 

and 1.0% CFC-11 appear in Figure 1. The data are well 

simulated by the model both during and postexposure., except 

at 0.1 % where data are slightly un&rpredicted. 

Chiou and Niazi, 1973. The model does a reasonable job 

of simulating venous concentration aftcr an intravenous injec- 
22 VINEGAR 

TABLE 2 

Physiological Parameters for Dog 

Parameter 

Tissue volumm (96 body weight) 

Slow 

Rapid 

Lrer 

Gut 

Fat 

Slow 

Rapid 

Liver 

Gut 

Fat 

SC~M parameters (body weight’”’) 

Aivmlar venhlation rate Whkg) 

Tissue blood flows (% cardlac output) 

carlilac output (Mg) 

54.8 

4.1 

3.3 

3.7 

15.0 

27 7 

32 9 

46 

25.1 

97 

8.0-33 4 

9.3-34.4 -~ 

Norr Tissue volume and blood flow parameter values based on Brown et al 

(1997). Scaled paramcax values raken from the simulation data wuws III this 

paper. 

tion of 28 mg of CFC-11 (Fig. 2). The model tends to overpredict venous concentration from 0.4 to 0.8 h and underpredict from 1.8 to 3.5 h. 

Arterial and alveolar concentrations are 

well simulated under changing inspired concentrations of 

isoflurane for dog 1 (Fig. 3). However, arterial concentration is 

consistently overpredicted for dog 2, even with good model fit 

for alveolar concentrations. 

Simulations are shown for arterial. venous, and alveolar concentrations during and after exposure to 

halothane and isoflurane (Fig. 4). Overlapping simulations are 

shown that differ from 100 min to the end of the exposure. 

During this time cod, the upper curve is a result of alveolar 

ventilation being set equal to cardiac output, while the lower 

curve results from alveolar ventilation being set equal to 10 of 

cardiac output (see Discussion section for explanation). 

Simulation of arterial concentration is 

shown during half-hourly, 0.5% stepped increases in inhaled 

concentration up to 2.0% (Fig. 5). Data shown at the end of 

each half hour are generally well represented by the model, 

although somewhat overpredicted at 2.0%. 

Wilhelnr (personal communication). Alveolar concentrations for desflurane and isoflurane are shown during and after 

exposure (Fig. 6). Desflurane and isoflurane data are generally 

well predicted both during and after exposure. 

Thoinas, 1975. 

Frei et al., 1988. 

Hughes et al., 1980. 

DISCUSSION 

Using ventilation and inspired concentration. actually measured during the course of an inhalation exposure, has been 

demonstrated to lead to successful simulation of pharmacokinetic data collected during the study. Exhaled breath concentrations of rats exposed to chloropentafluorobenzene were successfully simulated when measured minute ventilation was 

incorporated into the model (Vinegar et ul., 1990). Similarly, 

exbaled concentrations of humans exposed to anesthetics were 

successfully simulated on a breath-by-breath basis when ventilation and inspired concentration were incorporated into the 

model (Vinegar et al., 1998). 

The data used to validate the breath-by-breath dog model 

were collected under varying protocols, which resulted in 

variability in ventilation and cardiac output. The degree of 

reporting of the values of these paramcters also varied amongst 

the papers. Dogs inhaled CFC-11 while awake and spontaneously breathing (Am et a/., 1973), and were given intravenous 

infusion while awake and spontaneously breathing (Chiou and 

Niazi, 1973). Exposure to the anesthetics isoflurane (Thomas. 

1975). isoflurane and desflurane (Wilhelm, personal communication), isoflurane and halothane (Frei et al., 1988). and 

halothane (Hughes et al., 1980) was accomplished using mechanical ventilation. 

Hughes et a/. (1980) showed that cardiac output decreases 

by over 50% during the course of stepped increases in inhaled 

halothane concentration. Cardiac output decreased from a control level of 0.155 Vmin/kg to 0.125,0.122,0.084, and 0.066 at 

0.5, 1.0, 1.5, and 2.0% halothane, respectively. 

Ahlgren et al. (1978) exposed dogs to 1.5% halothane for 

either 30 or 120 min. Six dogs with average weight of 18 kg 

had a reduction in cardiac output from 2833 to 1630 dmin 

after a 30-min exposure to 1.5% halothane. A second group of 

7 dogs with average weight of 15 kg showed cardiac output 

dropping from 1827 to 1490 mYmin after 120 min of exposure. 

The 42% drop in cardiac output compared with control level, 

after a 30-min exposure. was comparable to the 458 drop in 

cardiac output seen by Hughes et al. (1980). also after 30 min 

of 1.5% halothane exposure. 

Dogs exposed to desflurane while spontaneously breathing 

showed cardiac outputs of 128, 115, and 96 ml/kg/min and 

respiratory rates of 37, 47, and 22 at end tidal exposures of 

10.3, 12.9, and IS.&%, respectively (Clarke et al., 1996). 

Measurements of respiration rate and tidal volume were 

made in spontaneously breathing dogs exposed for 40 min, via 

tracheal intubation, to 1.352 halothane or 1.95% isotlurane 

(Hellebrekers, 1986). They had previously been exposed to up 

to 4.54 of each agent by face mask in order to anesthetize 

them for the tracheal intuhation. Respiratory rates increased for 

both agents during the 40-min period, although the rates for 

halothane were generally nearly twice those for isoflurane. 

Larger changes were Seen in tidal volume, which initially 

dropped for 5 min, leveled off, and then started to increase at 

30 min with values approaching control levels at 40 min. 

Halothane produced greater decreases in tidal volume than did 

isoflurane. 

In light of the variability of ventilation and cardiac output 

during the exposures described, it is useful to consider the 
MODELING OF CA"E INHALATION EXPOSURES 23 

- 

CFGll ! 

1 0% 

iA I k i&] CFC-11 1 1 

CI I 

0 5% 

0 5 10 1s 20 2s 30 

25 

20 

1s 

10 

5 

0 

0 5 10 15 20 25 30 

> 

10 

6 

6 

4 

2 

0 

CFGll 

0.1% 

I 

-_ 9 

FIG. 1. Artend and venous concenIrahom dump and after inhalahon cxp 

CFC.11 (h et al., 1973). Continuoub 

SUE (#I = 4-5) to 1.0, 05, and 01% 

051015202530 0s1015202s30 hs represent nmulations. Actual data 

MINUTES 

difference in the behavior of the model, comparing default 

values for ventilation and cardiac output with values that take 

into account the changes that might result from the exposure. 

Of the data sets used, the most complete is that of Frei er al. 

(1988) (Fig. 4). Measurements of inspired, end-expired, arterial, and mixed venous concentrations wete made and reported 

for 160 min of exposure and 50 min of washout of the anesthetics halothane and isoflurane. Cardiac output was also measllled and reported over the same time period. Ventilation was 

maintained at 12 breaths per min. but tidal volume was varied 

to maintain constant arterial PaCO,. Periods of hyperventilation and hypercirculation were induced during the course of the 

experiment. The data provided in this study were useful for 

probing the effects of ventilation, perfusion, and ventilation: 

perfusion ratio (WR) on the ability of the model to simulate a 

@veri data set. Sinceicardiac output data were available, the 

anz plotted with bars representing one 

standard deviauon above and below the 

mean 

actual cardiac output was used in the model and ventilation was 

calculated based on the VPR. The actual arterial, venous, and 

alveolar concentrations do not show significant change during 

the course of the exposure, because the anesthetic was administered with a fcedback-controllcd delivery system. Howcver. 

initial simulations of arterial, venous, and alveolar concentration all show a sharp rise at around 100 min, which is when 

hypercirculation was induced with epinephrine. These simulations were performed initially with the assumption that the 

VPR was 1 throughout the experiment. However, the induced 

hypen5xculation does not necessarily result in a corresponding 

change in ventilation. Epinephrine has a profound effect on 

cardiac output but also results in increased ventilation. The 

increased ventilation would lead to reduced pCOl and according to the protocol, would have resulted in the tidal volume 

delivered by the ventilator being reduced to allow a return to 
24 VINEGAR 

T 

=I 0 

4. 

- E 

z 5 0.1 

x 8 0.01 

W 

CFC7 -11 I 

28mg IV I 

4 

HOURS 

FIG. 2. Venous mncentrabon followmg intravenous injecbon of 28 mg of 

CFC-I 1 to a 45 kg dog (chiou and Niau, 1973). Conhnuous line represents the 

simulation. Actual data are shown as individual pomts. 

normal pCO? levels. Setting the VPR to 0.5 during the period 

of hypercirculation resulted in the simulations more closely 

predicting the actual data (see Fig. 4, lower curves). Ventilation was mea3ured at times of sample taking for analysis, but 

the data were not reported. Ventilation and cardiac output are 

major contributors to the model's ability to simulate actual 

data, but another contributing factor may be the concomitant 

changes in the distributlon of cardiac output as a result of 

anesthetic exposure and of other manipulations, such as the 

intentional induction of hypercirculation reported in this study 

Ahlgren et al. (1978) presented data demonstrating effects of 

halothane exposure on the distribution of cardiac output. Significant changes were seen in flows to some organs. Data were 

presented for 30 and 60 min of exposure to 1.5% halothane. 

Unfortunately, there are not enough data to incorporate into the 

model. 

Although Wilhelm (personal communication) measured inspired and expired (end tidal and mixed) agent concentrations, 

respiratory rate, and tidal volume on a breath-by-breath basis, 

the only data provided were the expired concentrations at 

selected time points and the target inhaled concentration. However, the volume of anesthetic administered was also provided. 

This wa5 used to set the ventilatory parameters for the model. 

Fixing the frequency at 12 breaths per minute, a tidal volume 

of 185 ml provided simulated inspired volumes for hoflurane 

and desflurane of 9377 and 47,632 ml, respectively. The respective measured, inspired volumes were 9388 and 47,661 ml 

Using the ventilatory parameters determined in this way resulted in the simulations of alveolar concentration shown in 

Figure 6. 

Hughes et ai. (1980) exposed dogs to stepped increases in 

halothane concentration and measured cardiac output at the end 

of each half-hour exposure period. Cardiac output data were 

used in the model so that values for cardiac output were 

interpolated for times between the half-hour measurement 

points. The simulation uses the measured cardiac output as 

input in the model, and ventilation is derived based on a VPR 

of 1 (Fig. 5). 

3 01-1 I 

w 0.0 0.5 1 .o 1 .5 2.0 

k 

3 01-1 I 

w 0.0 0.5 1 .o 1 .5 2.0 

k 

v 

I- r--- 1SOFI.URANE I 

loo004 c mi i 

i 

w 0.0 0.5 1 .o 1.5 2.0 

f ZOM) 

I 

---..-.---1 

FTG. 3. Anend and alveolar concenIrabons during a varymg concenlratlon inhalation exposure of isoflurane to n 

ISOFLURANE 00 

1 

2 indivldual dogs-(Thomas. 1975) Con- 0.0 05 1 .o 1.5 2.0 00 0.5 1.0 15 2.0 

hnuous lines rcpresent yimulations. Acmal data are shown as indmdd points. HOURS 
MODELING OF CANINE INHALATION EXPOSURES 25 

HALOTHANE 

60 120 180 240 

0 60 120 180 240 

60 120 180 240 

YHUTES 

ISOFLURANE 

160 , 

0 60 I20 180 240 

FIG. 4. Amrht, venous, and alv~ 

lar COnCeI'ItratlOnS dunng and after mbalation exposure to halothane and mtlume (Frei er al , 1988). Continuous lines 

repesent sunulatlons. See text for expla0 60 

Development of a PBPK model is an iterative process involving model formulation, collection of pharmacokinetic data 

to test the model's structure, and often reformulation to account for any shortcoming of the model in simulating the 

collected data. Ideally, data collection should occur in conjunction with model development, with tbe modeler having considerable oversight on the quality and quantity of data collected. Often, the data requhements may go beyond 

pharmacokinetic samples but may include key physiological 

variables such as ventilation and cardiac output. There are 

times when it is necessary to develop and validate a model with 

data that already exist in the literature. This was the case in this 

study, where the model was already validated for use in humans but its use in dogs required obtaining results of published 

pharmacokinetic studies. At first glance, this might not appear 

to be a bad thing. Aftq all, one now has the opportunity to pick 

120 180 240 nation of simulatlon ks. Actual data 

YlNUlES 

(average of 6 dogs) are shown as avidual points. 

from a variety of studies, choose several, and demonstrate the 

successful simulation of the pharmacokinetic data presented. 

However, as a modeler, one quickly learns that not all data sets 

are created equal. Alas, experiments and data resulting from 

them are obtained to suit the requirements of the original 

author and not those of the modeler, who may come along later 

and want to borrow the data for model validation purposes. 

When, there are a number of papers to pick from, they generally fall into two broad categories: those from which the data, 

when modeled, are at least in general agreement with model 

prediction and those from which the data and model are in 

hopeless disagreement. Focus will remain on the first category 

where general agreement occurs between model and data. Then 

focus must tun to the details of the experiment. Wcrc the 

animals awake or anesthetized? If awake, were they active 

(excited) or resting? If they wcrc anesthetized, were they 

. -. 
26 VINEGAR 

artificially ventilated or allowed to breathe spontaneously? If 

artificially ventilated, what were the frequency and tidal volume settings of the ventilator? In actuality, in any one of these 

instances, frequency and tidal volume are hnportaat parameter 

values for the model. In many studies involving anesthetics, the 

respiratory frequency is often set (and reported in the paper) 

but tidal volume is varied (and not reported in the paper) to 

maintain pC02 withm acceptable physiological limits. Published studies with anesthetics often report in the methods that 

ventilation and inspired and expired anesthetic concentrations 

were measured on a breath-by-breath basis. Data such as these 

would of come be ideal for validation of a breath-by-breath 

PBPK model. However, these measurements are generally not 

the focus of the study and hence do not appear in the paper. 

One is then forced to make use of bits and pieces from various 

papers to determine what the range of acceptable values of 

ventilation and cardiac output could be under circumstances of 

the described experiment. Model predictions that may have 

been off by 308 or more often come into line with the data 

when appropriate adjustments are made to ventilation and 

cardiac output. 

The model did a reasonable job of simulating data obtained 

from a variety of experimental protocols. It is apparent that the 

absolute and relative values of ventilation and cardiac output, 

both of which vary as a result of exposure to anaesthetic 

agents, are important contributors to the degree of success of a 

simulation. With an understanding of how these two parameters vary, Monte Carlo simulation techniques could then be 

used to predict canine blood concentrations during exposure to 

selected chemicals. ‘I’hese values would then be the target 

blood concentrations needed for the human risk assessment 

I HALOTHANE 1 

E 

! z 

0 

F 300 4 

z 200 

8 

Eo 

0 

z 

100 

5 

PI: 

A 2.0% 

7 15% 1.0% 

i 

I 

1 

I 

1 k- 05% 

I 

Y 

4 0.0 0.5 1 .o 1.5 2.0 

HOURS 

FIG. 5. Artenal Concentrahon dunng stepped increases in mhalahon exposure to halothane (Hughes er 01.. 1980). Conhnuous lines represent simulanons Adual data (n = 6) are plotted with bars represenhng one standard 

deviation each above and below the meaa 

€4 

I8000 

I6000 

14000 

12000 

10000 

8000 f 

4000 6ooo! 

2000 

0 v. 

z 0 2 4 6 a 

w 

52 

6 

u 

100000 

80000 

60000 

I 40000 I 

DESFLURANE I 

8.94% ’ I 

20000 

0 I-.__. 0 2 4 6 8 

HOURS 

FIG. 6. Alveoh concentration during and after inhnlauon exposure to 

isoflurane and desflurane (Wdhelm. personal cornmumcation). Cmbnu~s 

lines represent simulabom. Actual data (n = 6) are shown as individual points 

process for detcrmining safe exposure to Halon replacement 

chemicals (Vinegar et al., 2000). 

ACKNOWLEDGMEiNTS 

The work wed herein has been supported by the Department of the An 

Force, Contract No. F41624-96-C-9010. by an interagency wment between U S.A F and U.S EPA #DW57937570-10-0, and by the Department 

of Defense (DOD) Next Generahon Fire Suppressloo Technology Propm, 

fundcd by the DoD Strategrc Envmental Research and Development Program (SERDP). Special thanks are given to 1. A Wilhelm, Ph D. of Baxter 

Anesthesia New Roridence, NJ for allowmg the use of unpublished data on 

desflurane and isotlurane 

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hemodynamic effect of halothane in the normovolemic dog. Acta Annestherrol. Scmui 22, 83-92 

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levels of fluorocarbon related to cardiac senmu7ahon. Am. Ind Hyg. Assoc. 

J.34,102-1W 
MODELING OF CANINE INHALATION ExPOSUREs 27 

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