Document 6wdxyjya3Qj9XQdrQp16aw4n3
NG MONTHLY
VOLUME 3 NO. 2
r
M
M ii international journal concerned with t * effects of chemicals on living systems
R&s 026302
Tisevier/ North-Holland, Amsterdam
1^1
r
..virology, '! (l'J7!>) 2-11 2T>2 K!si-vi-r/Norl)>-Holl:iml, Amsterdam I'riulwl m 11,. \.t i,,rlamls
TOXICITY OK AKROSOC IMlOI'KU.ANTS IN Till-: RKSI'l RATORY AND ' IRCUI.ATORY KYSTIOMS 'III. KKSI'IRATION AND ClRCDbATIO.N IN I'RIMATKS*
!>( iMINCiO M A VI ADO si ml DAVID OAliV SMITH
h' luirtmcnl of I'hanuurolofty. Imn-roly of /V/oi.vy/iwou, Srhool of M,;linin\ t ).:lnilcli>hia. I'n I'.IITI (t'.S.A.)
' !!-ri'iv*il -Junc l.'Uli, 1971)
I'.MMAHY
The low-pressure propellants influence predominantly Die circulation, v.-icreas the hit'll [iressure propellants affect the respiration in anesthetized c -Hikeys. There are four groups according to the level of toxicity: Class /, ; .-pressure propellants of high toxicity that cause tachycardia and hypo-
ion; Class 2, low-pressure propellants of intermediate toxicity that influ either circulation or respiration or both; Class 3, high-pressure propel1 - of intermediate toxicity that cause bronchoconstrietion, and Class 4. ` pressure propellants of low toxicity that do not influence respiration or
lulion even when inhaled at levels of up to 20% concentration.
DUCT i ON
far in this series of investigations the effects of 8 propellants have been tied in two animal species: 7 in the rat [7] and 3 in the mouse [4]. 3
propellants cause bronchoconstrietion and respiratory depression, and 'once only bronchomotor tone or respiration but not both. Since there o propellants that are being compared, the respiratory profile is still own for 7. For the sake of completeness, all 15 are presently compared monkey with measurements of respiratory minute volume, pulmonary 'mce and pulmonary compliance. The aortic blood pressure and heart *e also recorded to arrive at a general statement as to the comparative vity of the respiratory and circulatory systems.
irled by the Komi ;,n(! Drug administration under Contract No. I-DA 11-310.
2-11
$ o' r r> -I..
el
5x\
This is tlii1 third comparison of SU^I a propellants which has not hcci, hitherto attempted. The first, one was for the detection of pruarrhythmii activity in mice 11 ) and the second concerned depression of cardiac contrac tility in the monkey | 3|. The results were used to classify the propellanLs on the basis of their potency and the nature of the cardiotoxieily involved. The differentiation of the propellants on the basis of their vapor pressure was completely ignored. However, since recent events have prompted Lhe neces sity to discard some widely used propellants, the choice of substitutes would be facilitated if the classification would separate Lite hit'll-pressure propel lants from the low-pressure ones. The differentiation between the two is based on the vapor pressure and boiling point: propellants with vapor pres sure less than 31 psig and boiling point above -1 T' are low-pressure ones and those with a higher vapor pressure and lower boiling point are character ized as high-pressure. The elassifieation whieh is proposed below takes into consideration the pressure as well as the level of toxicity affecting the respi ratory and eirculatory systems.
EXPEUMENTAL MATKItlAI.S AND METHODS
Propellants administered hy inhalation The fifteen compounds are grouped according to their vapor pressure and
boiling point into high- and low-pressure propellants. All hut five are Chlo rinated and are identified hy fluorocarbon (FC) numbers which denote the position of the fluorine and chlorine substitution. The chemical structures of the compounds arranged in the decreasing order of the boiling point at oneatmosphere are as follows:
h-1 t'
h. r, . . /'A / /
I'. -J i '<i'l :l V1
h '-Y
ts-ni'
\ \ ' '
1
- /V
v *: >44
*rrichlorM*thjtrH'
KC 11.`}; Trichl<>r<tinnu<>r<M*ih,im' Methylene chlortde KC 11; Tnehloroflunromethanc KC 21; Dichlor'itnonofluoroimlham* fC 11*1; IhchlortUviTafUtoroethanL' KC C318; (IcLariuorncyrlnhutnne KC 1-12b; MonuchlornriifluurneihaiK' Isohutane
Hiuh;irrntturv prn/H'lltt:i/.
Vmyl chloride f*C 152a; DifUmroethanc KC 12; Ihehiorodifluorometh.tiu' KC 11 5; Chloropenunu<roetlune
pC 22; MonorhlorodiriuoMimetliane
propane
242
llniiinK point C
Vapor pressure
pain at 20*C
?4.i 47.0 *10,1 23.8
8.0 3.8 - 5.8 - 10.0 -10.2
-- 1 3.9 -24.7 -20.8 -38.7 -40.8 -42.2
-- 1 2.5 - 9.2 " 7.3 - 1.3
8.4 12,0 25.4 29.1 30.0
31.5 03.0 70.2 103.0 121.4 130.3
3D Bo CO
O
oN>J
jf
oU
Ltt
' ti P
51
With lh<! exception of KG 1 1, all of the compounds cxammcd exist in the vapor or gaseous phase at normal ambient temperature and pressure ami were therefore stored in pressure cylinders. The desired concentrations were attained by delivering a metered volume of the gas from the cylinder and diluting if with a known volume of air. The vapor of fluorocarbon 11 (boiling point 23.8) was generated by healing the compound in a water hath. The following concentrations were used: 2.fi, 5, 10 and 20G of tin*, vapor or gas in air. The mixture was administered for 5 min alternately with room air for 15 min.
Measurement of bronchopulmonary function Rhesus monkeys (Mucam mulatta), weighing from 1.8 to 2.7 kg. were
anesthetized by intravenous injection of 30 mg/kg sodium pentobarbital and the trachea was cannulated. Lead II electrocardiogram and femoral arterial blood pressure were recorded. Pulmonary resistance and compliance were estimated from measurements of tracheal air flow and transputmonary pressure. The tracheal cannula was connected to a mesh screen Kleiseh pneumotacho graph with a heating unit to maintain inspired air at a constant temperature, and the pressure difference across the screen was measured by a differential pressure transducer. The signal from the transducer corresponding to air flow was in turn integrated and recorded as tidal volume. Respiratory minute volume was obtained by means of an integrating preamplifier which con verted the flow measurements into volume.
The pressure difference between the trachea and the intrapleural space was measured with a second differential transducer. To determine pulmo nary resistance, the flow and pressure1 signals were displayed simultaneously on both axes of the oscilloscope screen to show a Pressure-Flow loop. Sub sequently an amount of pressure proportional to volume was subtracted, so that the loop was closed at zero flow. The slope of the line thus obtained corresponded to pulmonary resistance. The values for compliance were ob tained similarly by displaying the Pressure-Volume signals and subtracting pressure due to resistance, or by calculation front the subtracted pressure when closing the resistance loop [8].
RESULTS
The classification that is being used is based on consideration of the vapor pressure of the propellant as well as of the minimal concentration that influences the various parameters relating to the circulatory and respiratory systems. The 9 low-pressure propellants arc divided into two classes: Class /, those that influence cardiovascular function in concentrations of 2.5 to 5"; and Class 2, those that influence cardiovascular and bronchopulmonary func tion in concentrations of 10 to 20%. The 6 high-pressure propellants also are divided into two classes; Class 3, those that influence bronchopulmonary function in concentrations of 10 to 20%; and Class /, those that do not influence cardiovascular and bronchopulmonary function in inspired coneen-
ir mM-
2'I3
-4 $7.
R&S 026305
lration levels of up lo 20'/. For brevity, Hie concentrations are identified as follows: 2.f> to 5% to represent a high level of toxicity, 10 if) 20V as intermediate, and the low level for those that hail no detectable Loxicily when inhaled in concentrations of up to 20'/,,
Class I; l.oiu-pressure propellants of hit'll toxicity The 5 members are listed in Table I with their respective effects on the
various measurements. The characteristic features common lo till n propel lants are tachycardia and hypotension aL concentrations of 2.:> to 5//. I he effects on respiration are varied; two of them cause depression of respiratory minute volume, three an increase in compliance, and four a decrease in pulmonary resistance. 'Hie special features for each propellant tire as lollows: FC 11 causes the most intense tachycardia and hypotension. fC 21 is the most potent depressant for respiratory minute volume. FC 113 is second to FC 11 in the degree of cardiovascular effect, but FC 113 is more potent than FC 11 in decreasing pulmonary resistance and increasing compliance. T richloroethane is the propellant that causes a significant fall in resistance'and respiratory minute volume but an increase in compliance. Methylene chlo ride has no effect on respiratory minute volume but has the most potent action on pulmonary resistance and compliance.
Class 2: Low-pressure propellants of intermediate toxicity The 4 members are listed in Table 11. The effective inhaled concentrations
are 10 to 20%, which influence either respiration or circulation or both. FC 114 affects both and causes specifically tachycardia, hypotension, respira tory deptession and an increase in pulmonary resistance. FC 142b causes hypotension but also respiratory stimulation, an effect that is unique, since no other propellants belonging to this class or other classes exert such an action. Isobutane does not influence circulation but increases resistance and depresses respiratory minute volume. FC C-318 causes an increase in resis tance but has no effect on minute volume, heart rate or blood pressure.
Class 3: Iligh-pressure propellants of intermediate toxicity The characteristic feature of the 4 members is an increase in pulmonary
resistance or bronchoconstriction (Table 111). The additional effects vary among the propellants, as follows: FC 12 decreases compliance, reduces blood pressure and accelerates the heart rate. FC 22 does not decrease com pliance but influences the other four parameters. Propane has the mi<st limited influence -- only bronchoconstriction and respiratory depression. Vinyl chloride affects all three respiratory parameters but not circulation.
Class 4: High-pressure propellants of low toxicity The 2 members listed in Table IV do not influence respiration or circula
tion, even when inhaled in levels up to 20%. concentration.
DISCUSSION
The most important conclusion drawn from the above experiments is the
244
-I tfl S c
o O S': 5- C? = 2. S'
if-#11
TABLEI
Propellant
Pulm. resistance
vtv No.
Couirol
Response *7 A
cm H;0/l/scc
Pulm. compliance
Control
Response
ml/cm tl ;0
7A
llesp. min. vnl.
Control ml/mm
11 espouse
rr-i
FC 11 (Trichloroflu tirnmelhane)
FC 21
2.5
( Diehl or o*
fluorome thane)
5.0
FC113 (Trichlorotri* fluoroe thane)
2.ii
Thchlnroethane
Methylene chloride
2.6 5.0
4
3 3 :i 3
3 3
a;i < {>.05.
2S.fi * 1.0
35.3 t 2.3
* 2.2
32.7 1.00
21,78 ? 3.4fi
21.58 ' 3.00
20.38 * 2.5fi
21.22 * 2.00
20.38 2.5fi
22.83 * 3.72
07 <> 0.7
33.0 ; 3.1
27.2 *- 1.4
20.4 1.0
10 fiO 2.71
18.R4 . 2.4 7
18.52 t 2.11
1 8.08 : 3.04
18.53 3.43
13.72 - 3.83
- 2.00 ~ 2.00
- 7.00 I 4.00
- 2.0i> : 2.00
--io.swv' * 1.00 - 8.87 - 4.7 5
-12.07 * fi.l> 4
- 8.87 1.0" -15.43 2.30
-- 10.43 i 7.80
--32.08 1l 2.83
7.fi -.0.7
7.0 ` 0.1
7.7 : O.fi
7, \ - O.fi
fi.87 0.4 3
fi.fi 7 0.58
7.20 0.72
T.Ofi 0.5fi
(>.90 : 0.38
fi.00 t 0.5fi
7.3 i O.fi
7.4 0.4
7.8 1 O.fi
8.0 0.7
7.27 - 0.41
7.50 0.25
7.80 0.7 2
8. 1 fi - 0 71
7.fi 3 : 0.4 7
R.2fi 0.30
+ 3.00 *- 3.00
fiOil : 107
+ 7.00 - 4.00
+ 1.00 t 1.00
fi 12 - 142
442 50
* 8.00 . . 1.00 :>.07 2.30
+1 3,0 5 * 8,80 + 8,40 - 1.55 + 15.52 3.55 *10.00 - fi. 1 8
- 5.00
4 55 01
12.10 . 4 7.3
1 202 - 00
1352 30.3
1352 30.3
1280 111
1300 - 100
744 * 238
541 104
274 L fiS
203 24
1230 t 28.0
1302 ' -
12 13 32.1
1183 11.0
124 7
1 227 37
* 4.00 i 4.00
- 0.00 ; 1.00 -39.00 : 1 0.00
Sd.Dl!-' - 0.00 * l.ftit 1 80
> I.IO - 3.20
8.11
-12 1J * 2.1
- 5.00 * 4.20
ztssjztt&j
10Z9Z0 S9U
^5g_
**
wwirr~> m-mk>
ffilll^.,lJtt,5C.
to TABLE ] <rontinueil>
O Propellant
* Cone. Mon Wry Heart rale____________ ___
v/v N'o.
Control
Response
bcaU/min
KC 11 tTrichioTsj* fluoTOiriftHaneJ
2.5 5.0
KC 3 L
2.5
fluoranM'thsiiH') 5.0
re 113 (Tnchlorolri-
fhicmielhaiu')
2.5 5.0
mdilonv i-lharu'
2.5 5.0
MvtbyU'ne chloride
2.5 5.0
3
4 3 4
3
3 3 3 3 3
183
175
145
150
*. Vi 109 i wo 5
(73.33 * 1 2.02
175.00 * 13.90
17 5.00 10.90
174.33
15.31s
174,00 *. 12.00
213 10
239 23
108 : 32
177 : 17
100 \ 19.00
22 l .07 21.07
182.00 13.53
202.00 - 8.07
1*7.33 * 18.7 0
205.00 ? 0.09
+1 0.00 i 7.00
+ 30,DO'1 * 1 0.00
+ 1 5.00 * 10.00
* 17.00 5.00
+ 18.07 * 8.14
*27.85'' ; 8.58
* 4.23 - 4.20
-t 18.13* * 7.75
* 7.00 1.23 * 18.0 S'1 0.88
t Ml! U
mw--*""frW>Wilini . *"V 1
806920 S9U
r.\Bi.K [i .w,,uru
* Cone. v*v
M..nk,y N*.
Pu'm.
Control
Kc*pori*c
cm H;OA/*t'C
CITY 1MKAX * SKM1
---
pt:Im. complUnov
'>-1
Control
Ucs.pl>1
ml cm 11;*1
ye in
(DiclilorotciM*
flunroelh-tnej
50 10.0
20.0
KC 1 *2t> (MonneUWorlifUmnielluru*)
5,0 10 U
3 i
5.0 10.0
3 .1
VC 1*31 8 i tcHibuI.il.c1
5.0 10.0
.1 I
21.70
* 1.7 4
10.75
0.80
22.4 2 2.JW*
28" --
0.7
21.3b 1.81
21.11 1.5*'
20.1 * l.-l
28.2 * 0.-1
22.0.1 1.71
20.80
' 1.31
25.07 * 3.7ti
28.7 * 2.5
20.7 0.7
22.77 1.75
25.05 3.0H
20,-1 1.4
32.3 : 0.8
1.58 * 1.50
+ 5.58 * 3.3 2 4 11.38 - u,n 1
0.0 0.0
0,0 o.o
* 0.7 5 2.38 + 10.30 10.70
0.0 * OO
*13.0 * 2,0
0.83 o.oo
0.00 `0.515
0,03 1.17
8.30 - 0.1
7.1 0,0
ii.30 -41, |(!
0.83 O.l*
8.8 lO
3.1 13
i>,77 O. 13
ti.KH `0.37
5.0 7 * 0.0 \
8.30 n. 1
7.5 - 0.0
0.3 3 - o.OO
0.37 O 03
8.3 - 0.8
7.n - 0.8
0 05.
.------- -
7i
---mm. v>1.
--
Control
He spoil sc
nil .'mm
7i
*p | o
-1.18
7.78 0,80 0.0 O0
OO 0.0 2.70 2.7 0 0 70 7.3 8 3.00 .1.00
1.00 1.00
mo 52
1307 V1
l 184t 30 1
3 13
187 82
U lO 2*> 120.03
1370 HU 103 t(
1 13 r>
\ .30 V - 1 u\
1.170 1 23
1217 77,0
too 20
3 32 - Ml
1301 i-7 IV' 8d
12 31 .*>7 - IP 1
nr 13
38
1.8 1 ' 0,80
8, 1 7 0.20
1 7,01V1 O.JH
* 10.0`* 3O
. ii n - (i l>
3.7m - 3 12
l.t 3b - 3 01
- 1.00 \ oo
3 410 - 2.no
609Z0 S'Sy
js*saotfta
aaF
.ayasre;
. rt.
A
248
TA8LE il (continued)
Propellant
% Cone. V/V
Monkey No.
Heart rate
Control beatsfmin
Response
''r-l
Aortic blood pressure
Control mm Hr
Response
r~r
KC 1 14 (Rie'nlorolrtraflu nro ctlnine)
5.0 10.0
ao.o
3
3 3
IfiS.OD i 13.58
l 7 0.00 14.42
173.3.1 ; 12.35
180.07 : 6.36
1B8.58 : 7.20
212.00 r 2.00
+ 8.6 1 ; 7.70
+ 11.00 i 7.05
* 7.13
118.33 t 3.33
1 16.33 5.36
l t 1.33 : 3.67
114.33 ; 1.20
-3 27 ;2.10
105.00 r 5.77
8 7.03 ; 3.71
-9.78 2.14
2.56
VC 1-12b (Monorliloro* di rtuoror(bam*)
:>.o KU)
3 -1
1 8lp * 11
ISO * it
188 :0
183 *9
+ 1.0 ' 1.0
+ 2.0 r 1.0
<11.7 t <1.3
03.8 * 0.9
89.3 8.1
90.0 - 7.4
- 2.00 1.00
-- 6.00 : 3.00
Isobutam'
5.0 10.0
3 3
172 1 5 >>rt
182.00 : 11.00
177.33 : 6.43
nu.oo * E.72
+ 3.00 0.02 + 6,85 : L.89
] l 5.6i r 4 70
1 1 7.3 3 - 5.01
113 2.08
9-1 3.79
- 2.13 2 13 -21.60
1.08
vc c-:n 8
5.0 3
(f)clafluoru-
118 * 20
154 - 25
+ 3.0.# t 3.00
80.0 2.0
79.0 3.2
- 1.00 ' 3.00
evcUtbulartcj
_____ .,,____
10.0
4
140
L 50
12
14
-- ------------------------------------
+ 3 00
80.2
86.0
: 2.00
7.0 : 7.3
-- -------------------- --- - - - ----------- --
- 1.00
. 4 00
--
Of-920 S9U
table hi
HIGH-l'HKSSUUE PROPELLANTS OK INTERMEDIATE TOXICITY (MEAN SKM)
PrnpeUaiil
'c Cone. Monkey Pulm, resistance
Centred cm tliOf LFS
Response
'rS
Putm. compliance
Control.
Response
nOr'cm 11 ;ll
'll
FC 12 (Dichlorodi* fluoromethane)
5.0 10.0
KC 22 (Monochtoro-
10.0
tiiDo OTom c th a nc)
20.1)
Propane
10.0 20.0
Ym>l chloride 2.5 5.0
10.0
3
4 3
3 3 3 3 3 3
2ti.9 * 1.2
20.1 *- 0,9
20.4 a ; 0.90
19.73 i 0.04
21.71 r 1.2-1
20.54 * 1.4)
21.4 1 : 0.41
20.70 r 0.35
20.00
28.tJ i 2+fi
33.5 t 1.2
21.57 ! 1.2R
23. 82 t 0.59
22.08 * 1.02
22.57 - 1.29
21+Kl t 0.41
21.98 0.23
23,07 0.97
+ 5.0 * 5.0
+ 15. O'* 2.0
+ 5.55 5.55
+ I5.8!V' : 4.8.3
+ 1.85 : 1.85 + 10.3.3 * 2.82
+ 1.70 * 1.70 0.20 *. 0.73 + 15.ns* * 4.8.3
9.7 0.9
9.0 * 0.4
0.83 *0,83
7.13 *0.90
0+23 0.67
0.50 * 0.50
0.30 *0.85
0.33 .O.K8
0.3+3 0.88
9.0 t>,0
8.0 *0.4
ti.lSG *0.00
0.0 5 *0.7.3
0.1 3 0.73
0.00 * 0.70
0.27 0.88
4.5.3 0.84
5,90 1.23
- 0.0 0.0
-11.0 * 0,0
~ 1.90 : 1.90
O.40 : 2.80
- 1.84 : 1.11 -- 7.22 * 5.04
- 0.00 0.00 * 2.91 * 3.50 - 8.01 t 0.49
a v < 0.05.
Kesp. min. * >1.
Control ml,'mm
Response
'E+i
500 03
511 * 05
16U9 i .312
1503 *. 270
1380 t 99
1.394 * 1.32
1417 : 44
1355 * 108
1.380 12
500 * 03
+507 * 09
1 598 : 328
t 377 239
1+727 110
1 127 *. 11\ 8
1 107 i 72
1274 89
1211 10
`
0.00 0.00
- 1.00 2.oo
- 1.00 1.90
~) 1.70 1.50
-- 8.02 * 2,32 - 20.1 0 1.80
- 0.80 2.10 -- 5.80 1.00
12.30* * \ 20
.^$SSL *rz , *^920 ssy
a
250
TABL.KH1 (continued)
Pr opr)Jam
T Cone. v/y
Monkey No.
Heart rate
Control boats/mm
Itesponse
-7-A
FC 1 2 (DicKlorodinuoromelbane)
5.0 10.0
KC 22 (Mmmchlom-
10.0
<1iriuoronH'thaiHa)
20.0
Propane
10.0 20.0
\'iin 1 rhlunde 2.5 5.0
10.0
2
4 3
3 3 3 3 3 3
133 ; 13
14 7 ;0
Id7.ll0 10.10
1 n 7.3 1 - 15.07
170.33 * 3.18
173.33 3.3 3
171.33 - 5.03
17 1.33 * 5.03
17 1
1 10 8
J 70 -"
174 10.00
1 84.00 ' 18.50
171.33 3.18
180 0
1 71.33 5.03
173.00 7.23
1 78
+ 13.00 - 7.0(1
+ 10.00:| 4.00
+ 3.78 - 0.51
M.0! 4.75 + o.no
1.22 ^ 3.!'2 i.on
o oo
o.n2 0.02 * 2.14
Aortir blond pressure
Control mm llg.
H sponge
81.7 0.0
74.3 0.7
84.0 * 5.2
1 It : ;i
72.2 n.i
M0 3
1 1 2.33 1.4 5
1 1 7.00 3,0 3
M7.no * 3.38
1 1 5.33 3 28
1 to.no 3.21
1 10.3.1
oi .no ' 1 t .lid
i in 1
11 o.nn 2.3 3
M l 33 2,33
11 i.nn 3.28
i oo.nn
f- hi
TABLE IV HIGH-PRESSURE PROPELLANTS OK LOW TOXICITY (MEAN i SEM)
Propellant
% Cone. vfv
Monkey No-
Putm. resistance
Control cm H>0/ LPS
Response
<*.1
KCiia (ChloropcnlaDunrnetlianr)
lo.o 20.0
KC 152a
10.0
(l)i (Untrue thane)
20.0
3
3 3 4
23.36 * 2.10
22.00 i 2.03
26.90 i 1-GO
20.30 (.*10
23.26 t 2.16
23.00 J- 1.19
26.90 i 1.60
29.70 * 1.80
o.on 0.00
*2.02 2.02
o.oo 0,00 2.00 i2.no
Pulni. compliance
Control
Response
mUcm II;0
'r.i
6,07 0.07
6.07 0.07
7-80 1.10 7.10 0.60
6.07 - 0.07
ii.io 6.21
7.80 ; 1.10
7.10 - O.f.O
0.00 0.00
0.59 3.87
0.01) o.tm 0,00 0.00
Resit, mm. vol.
Control ml,min
Response
'li
1473 93
l 3**0 123
783 * 140
633 96
l 173 93
1 322 1 ,\6
767 t 12 587 117
0.00 0.00
- 5.40 *2,70
-2.00 1.00 - 9.00 6.00
TABLE IV (continued)
Propellant
*7 Cone. Monk. Wt No.
Heart rate
Cimtro1 hcapt/min
kespm .sc
ns
KC 11 5 (Chloropenta* fluo roe lhaiu*>
10.0 20-0
KC t 52a
10.0
(Di nuorovthejie)
20.0
n
3 3 4
183.33 * 11.79
185.33 *. 13.13
183 *3
182 :5
182 ; 10.58
186.00 t 12.43
183 *3
182 :h
+ 1-49 *0,94
+0.42 *0.42
0.00 0.00 0,00 0.00
.\nrttc bl< >mt presstirc
Cm/iimI imn If*;
lie-pnn\c
na
120-66 4.33
121.66 t 5.24
0.80 1.6 7
120.66 3.38
07.30 7.90
98.00 7.70
nn.33 3.81
97.30 * 7.90
98.00 7.70
-1.05 *2.73
0.00 0.00 0.00 0.00
251
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different in pattern of action liciween tin- two groups of propellants. Tin low-pressure propellants influence predominantly circulation and the high pressure ones affect respiration. The extent of action is not limited to one function, because there are a few propellants from each group that also influence those of the other group. For instance, the most potent lowpressure propellant that causes tachycardia and hypotension, i.c.. FC 11. also depresses respiration. On the other hand, the most potent high-pressure pro pellant, which depresses respiration, increases resistance and decreases com pliance, i.c., FC 12, also causes tachycardia and hypotension. About half of thi' low-pressure propellants also influence respiration, and a third of the high-pressure propellants also affect circulation.
The second conclusion can In' derived from an examination of the four tallies which list the classes of propellants. For each pressure class, there tire two levels of toxicity, The highly toxic class of low-pressure propellants includes FC 11 and trichlomcflianc, which are suspected of eau.smg deaths 12,5,9] following the use and abuse of aerosols. The low-pressure propellants of intermediate toxicity include -1 possible substitutes in the event that a decision is made to dispense with one or all 5 propellants that are in the highly toxic class.
The high-pressure propellants consist of four propellants of intermediate toxicity. One of them is vinyl chloride, which lias been banned for use in aerosols because of the reports or liver cancer among workmen exposed to this chemical [6]. The two high-pressure propellants in the low-toxicity class can be used as substitutes. It should be emphasized that the level of toxicity is based on results in monkeys reported in this publication. The results obtained from earlier experiments are commented upon in the next two papers which conclude this series.
REFERENCES
1 D.M, Aviado and M.A. Belej, Toxicity of aerosol propellants in the respiratory ant! circulatory systems, 1. Cardiac arrhythmia in the mouse. Toxicology, 2 (15)7-1j 31.
2 M. Hass, Sudden sniffing death, J. Am. Med. Assoc., 212 (15170* 207.">. 3 M.A. Belej, D.G. Smith and D.M. Aviado, Toxicity of aerosol propellants in the respira
tory and circulatory systems, IV. Cardioloxiciiv in the monkey, Toxicology, 2 (15)7 1* 381. `1 U.S. Brody, T. Watanahe and D.M. Aviado, Toxicity of aerosol propellants in the respiratory and circulatory systems, 111. Influence of Bronchopulmonary lesion on cardiopulmonary toxicity in the mouse, Toxicology, 2 ( 15)7*1) 173. 5 Federal Register: Triehloroethane (1,1, 1 -Trichloroethane, Melhylchloroform) Aerosol Drug Products for Human Use, August 1*1, 1973, 3S (|.rtj) 21 935-2193<>, (> Federal Register: Vinyl Chloride Containing Sell' PressurUed Products, May 9, 197-1, 3(1 (91) 16ftI M6512. 7 8.A. Friedman, M. Cammarato and D.M. Aviado, Toxicity of aerosol propellants in the respiratory and circulatory systems, II, Respiratory and bronchopulmonary effect in the rat. Toxicology, 1 v l3) 3-t5. 8 A.M, Klide and D.M. Aviado, Mechanism Tor the reduction in pulmonary resistance induced hy halothane, J, Pharmacol. Expil. Therap,, 1 r>8 ( 19(>7) 28, 9 G.J. Taylor and W.S. Harris, Cardiac toxicity of aerosol propellants, J, Am. Med. Assoc., 21 *1 (1970) 81.
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