Document KJe7KK6maM28xLKkX68kD0nLx
AR226-2745
EFFECT OF FLUOROCARBON DISPERSING AGENTS ON THE LIVERS OF RATS AND DOGS
-61
^
Report No. 123-65
&
ars powerful surfactants. In acute
oral toxiclty studies witlfthese compounds, the most striking
abnormality in animals surviving a single sublethal dose was gross
enlargement of e liver^kBUritfMMB^^(IMMBMltfiB
A siroflar
less marked effect was observed
in rabbits tha^ 'had absorbed'
through the skin. Although liver
enlargement 1 not an uncommon nding in chemical intoxications,
the effect of
'was remarkable in that 56 days after a single
dose of 12 n
the liver was approximately three times larger
than normal.
The experiments reported here were preliminary studies designed to determine more details concerning:
(1) the hisfcological changes, that occur with Increasing periods of time^. in the livers of rats after a single
oral dose otftRg
(2) the biochemical changes during the period of rapid
growth and recovery in the livers of rats treated
withjoQ
(3) the combined,effects of oral administration of
ethanol and u in the rat;
(4) the effect cf fi--7upon the pentobarbital sleeping time in the r.at; and
the effect on liver emotion in dogs treated with ^AMIteBritf----win order to find some clin
ical laBoratory procedure that might be useful in
detecting liver injury in personnel exposed to
fluorocarbon dispersiiig agents.
I. HISTOLOGICAL CHANGES DURING THE TIME OF RAPID GROWTH
A. Proced^ire; In order to study the changes in a^zeand structure of t; ^"Tiver following a single oral dose off--fj 14 male rats were each c;lven a dose of 12 mg/kg. A second group of animals of the same age and weight served as controls. One test and one control animal were killed at Intervals over a period of 56 days and two test and two control animals at 75 and 128 days. The livers were removed, weighed and a section taken for microscopic
Qxamination.
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B. Results; The rapid growth of the liver, in cerros of both weight and per cent of whole body mass, is shown in Figure 1. The increase in size was most marked during the first ten days, reached a maximum betwesn 40 and 60 days, and then began t.-- decrease in
size, although some enlargement was still evident after 128 days.
Morphological changes in the liver were evident 24 hours after
the single dose. The initial change was characterized by markedly
enhanced mitosis of the hepatocytes. This was less evident by the second day; by the ninth day, the roifcotic activity had decreased. After the j6th day, most of the features which characterized the response were less Intense.
The structural changes in the cells were quite evident upon microscopic examination and appeared to result principally from an enlargement of the individual cells.
II. BIOCHEMICAL AND METABOLIC CHANGES IN RAT LIVER
1. Changes in the Liver of Intact Animals
f_y^as
Procedure: a. single
Thirty male ChR-CD rats oral dose. Two to three
were weeks
given 12 nig/kg
later, eight of
r-ats were sacrificed by decapitation, the livers removed,
weighed, and analyzed. An equal number of untreated controls were
examined to establish the normal range of values Jbhat might be
expected in rats of this age and strain. Two^----Jtreatedrats and
two the
controls tissue.
were also sacrificed for Eight to ten weeks after
mthiecrossincgolpeic oerxaal mdionsaetioon^^--of--_^J
a second group of ten rats was sacrificed and the remaining ttSTT
rats three months later. Tissue slices were prepared from a
portion of the median lobe for respiration and choline oxidase
measurements in a Warburg respirometer. One portion of the left
lateral lobe was homogenized for measurement of alkaline phos-
phatase activity (APase.), esterase activity, and the nucleic acids.
Another portion was used for glycogen determination. The remain- .
ing tissue was used to measure water, protein, fat, ash, chol
esterol, phospholiplds, and potassium. An average value was
calculated .'*->r each group of animals and compared with the controls.
Differences uetween groups were tested for significance with the
"t" test.
B. Resulta: The results of the biochemical measurements are
given in TaDie i. TWO weeks after the single dose off----^ the
livers of the treated rats were quite large in size, morethan twice that of the controls, and comprised approximately 9^ of the body weight. An increase in the alkaline phosphatase activity and phospholiplds and a decrease in glycogen were the most important changes. Small but statistically significant (p^O.O^) increases in oxygen consumption, non-protein nitrogen, water and protein and decreases in the respiratory quotient, choline oxidase, RNA
and DNA o c curre d.
Two months after the single oral dose oflS^the livers were ?io longer growing at an accelerated rate, for-fchere was no further increase in the absolute size of the liver and its portion relative
SSrI^^ed.Dces not confer 7SCA CS.
to the whole body had decreased. The increase in phosphollpids, protein and non-protein nitrogen, and decrease in glycogen respiratory quotient, RNA and DNA again was observed.
li-3 Five and one-half months after the dose ofi----J the livers of
the treated rats were still slightly larger thainrm-noonnrnal, but the
small differences in the biochemical measurements were no longer significant.
I f These results indicate that^----jproduces significant bio
chemical as well as morphologicaKchanges in the liver of rats. A
number of these changes point to disturbances in the normal meta
bolic and synthetic functions of the liver. The lowered concen tration of nucleic acids is consistent with the observed arrested mitotic activity. These effects are most evident when the liver is rapidly increasing in size. Later, when the accelerated growth has slowed down or ceased, a reversal of biochemlcaL changes is apparent. Five or six months after the dose of ,1 when the liver is nearly normal in size, the recovery of the orgarTTLs virtually
complete.
2. Biochemical Changes and Liver Enlargement in Hepatectomized Rats
[dipt A;;_Procedure: To study the effect ofylJon liver tissue
already in a state of rapid growth or regener'ation, six male ChR-CD
rats were subjected to partial hepatectomy by removing 60 to 70$? of
the organ. Forty-eight houc& afiber the operation; the rats were
given a single oral dose of
12 mg/kg. The experiment was
also conducted reversing thebraer of treatment by remo\dng 60 to
70^ of the liver of rats which had been treated wa-bh^tjW hours
previously. Sham-operated animals dosed with/UB^nohepatectomlzed
animals-aerved as controls. Fourteen days after the single oral
dose of/----,| the livers of the rats were removed, weighed and
analyzed-To:r glycogen, phospholipids, DNA, RNA and alkaline phos-
phatase activity.
withffj B. Results; The results of these experiments are shown in
Table 2. Two weeks after the operation, the livers of the
partially hepatectomlzed control animals were normal in size for
rats of this age, sex, and strain, but the alkaline phosphatase
activity and DNA were higher than in noro&L livers. When partially
hepatectomized rats were treated
the livers grew very
rapidly; two weeks after treatment wiw the trimer, the livers were
more than twice those of the hepatecfcomized controls. The phos-
pholipid content and alkaline phosphatase activity were Increased
while the glycogen content ^deoaaeased. The DNA was again decreased
as in the livers of intact/iy treated rats, but the RNA had
increased. Except for thiB"increase in RNA, the results.wece in
agreement with the previous measurements on livers fromjOMtreated
rats shown in Table 1. The biochemical changes in the 4-tveT
occu
ment
r
red whether withIfiSSE^a
l
p
th
artia
ough
l
t
he he
pa
e
tec
ffe
tom
cts
y
p we
re r&
c
ed
so
ed
me
or
wha
t
f
ollow less
ed
wh
e
tr
n
e
a
t
hepatectoreyfollowed the treatment withf
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3. Effect of Chemical Injury on HBBjtreafced Rat Livers
A, Procedure
dose of 12 mg/kg o^ lethal dose of<Wl 100 gm of body weight
male ChR-CD rats were given a single oral id then, 48 hours later, a single sub----------|H equivalent to 0.1 ml per raperitoneally. Animals which received served as controls.
B. Results: The results of this experiment are also sho
in Table $'.--Qne~of the six rats dosed with gHftBB|||M|HMll
d'-ihede^^ei^ghMt ldWay--s l--atefrt,^Jdbuiteadllwsitihxinrat4s8
treacedwitn/----prior hours. No analysis of
bo
the Tiver was possible,Tor all of the animals were found dead and
post-mortem changes had begun. When examined grossly, however, the
livers were massive in size, approximately 50 to 40 gm, and yellow
in color, probably from acute fatty infiltration. The rapidly
enlarging liver, with a greater than normaly. llp^d;glycogen ratio,
is more susceptible fco the toxic effect of----mithan normal liver.
^^^k ^^~
ff-------- Biochemical measurements on the surviving
rats showed no appreciable differences from controls two weeks after the treatment.
ADMINISTRATION
IN THE RAT
^^UWSHSl^0^6 ofy^rrhe A. Procedure; The study was designed as an additional
evaluation of the effects of combining hepatotoxic agents. The
objective was to determine, by oral admini atration to rats,
whether repeated sublethal doses
enhance
the effect of a single hepafcotoxic dose
outline of
the study, in tabular form, is presented inTTable 5.
Male ChR-CD rats, weighing between 500-400 gm, were used in the study. They were offered water and Purina Laboratory Chow
on an ad libitua basis and were weighed daily.
At the time of the prescribed sacrifices, the animals were
subjected to gross pathological evaluation. The liver was removed, weighed, and preserved in appropriate fixatives.
to^fiffffffj B. Results: A summary of the liver weights obtained at the
various scheduled autopsies is^gi^en in Table 4. The preliminary
results of this study, wherein)----Jwas administered to rats in a
single dose of 12 mg/kg,^simulbaneously with, or after, their
exposure
indicate that the increase in liver
weights obs^Tveflinthis' experiment was not any greater than that
produced by|^|Nalone at a dose of 12 mg/kg.
IV. THE EFFECT
UPON PENTOBARBITAL SLEEPING TIME IN THE RAT
A. Procedure; Changes in liver function or liver morphology
have served as traditional indicators of hepatotoxiclty. More recently, a quick and simple pharmacologic test has been developed
C&^pan]? Sanity- Cocs ;^coni-n TSCA C^
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II
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which has be'en used to determine liver damage
Sleeping Time (PST).
Pentobarbital
Pentobarbital is metabolized in fche liver; a change in particular liver enzymes is reflected by a prolongation, or shortening, of the sleeping time induced in animals by this com pound's normal anesthetic action. Therefore, alteration in the PST has been correlated with changes in liver function and liver
morphology. When young adult male ChR-CD rats are given 50 mg-kg Na pentobarbital in an aqueous solution intraperitoneally, their average sleeping time was found to be 58 + 19 minutes (for 110
rats).
c- In studying the effect ofH----)administration upon PST, groups
of ten rats were employed. A CBnCrol value for PST was obtained
for each group of ten rats, usually 24 hours before the test began.
JTwi qnty-four- hours later, the rats were given a'single oral dose of
----yat the rate of 12 mg/kg. PST was determined on each group of
rare four hours, 24 hours, 48 hours,-and at other time intervals
afber the oral administration of fcheH--J Control groups were
.
similarly examined for PST at the samyCInie intervals. The results
of two of these tests are summarized in Table 5.
B. Results: The PST of rats that received^--Jwas first
prolonged; it then became shorter and shorter unCTI, at approxi
mately six days after dosing, none of the rats could be anesthetized
by a dose of Na pentobarblfcal that still affected untreated rats.
Approximately seven weeks later, the PST ofj--ytreated rats could
again be determined, but it was still much sfrorter than that
observed in control animals. The same observations were made for the next two weeks, at the end of which time the experiment was
terminated.
V. EFFECT OF PLUOROCARBON SURFACTAMTS ON LIVER FUNCTION IH DOGS
A. Procedure: Three male-beagles from the stock colony were
given a single oral dose
equivalent to 4, 6, or 9 nig/kg.
ofjfj Samples of blood were taken-afc"Frequent intervals for three weeks
and then weekly thereafter. The dog that received 4 mg/kg was
later given doses of 26 and 60 mg/kg. Fourotheryaale beagles were
given a single oral dose of eitherJAJBMBMBIBBI equivalent to
430 mg/kg and a sJuaHar&eries of tasuremenfcs^naae. Since both
thei|f|died dogs receiving
within 48 hours, the experiment was
repeated with two oSnerdogs which were given a 200 mg/kg dose of
thia.disgers3.ng agent. The two dogs that survived the exposure to
the1Kdwere gl^1'1 an additional oral dose, equivalent to 670
mg/vS--siT1 this time.
The following biochemical measurements were made routinely on the blood: sugar, urea nitrogen, totalyAha3desterol and alkaline
.phospteyfcase. When the 60 mg/kg^do se^fyff^j 470 mg/kg dose of
OBB^Ror the 670 mg/kg dose of]|Bl8iwere administered, fche level
.S''IrCaDcHr),ivaitlydoolafsela, cgtiluctadmehicydoroxgaelwaKcreetic(ED(GHO),T)isanodcigtrluictamdiechypdyrorugevnicase
(OPT) transaminase were also measured. A routine hematological
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examination and an analysis of a 24-hour urine specimen were made at intervals on these animals.
The level of the various components of the blood following the dose of fluorocarbon dispersing agents was compared with an average value observed prior to the exposure and with a similar measurement made at the same time on specimens from stock colony
dogs.
For the enzyme activities, a normal range was established from measurements made on a number of stock dogs. The activity was also measured at least once, prior to treatment, on the dogs
dosed with the dispersing agents.
B. Results: The significant biochemical and clinical findings are summarized briefly in Table 6.
The principal findings-indicative of some injury or dysfunction
in the dogs that receiveqjCffwas a decrease in the plasma chol
esterol and an increase in Sromsulfalein retention (BSP) and APase
activity. The effects on cholesterol and APase are shown in
Figures 2 and 5. These began to change within one week and became
"abnormal"
deviations
,
f
iio.me
.
, t
h
e e
x
cee pre
ded -exp
an
os
ar
ure
bitrar
mean
y w
limi
ithin
t
t
of hre
tw
e
o stan
weeks
dar
aft
d
e
r
the
dose was administered. The increase in BSP retention occurred
during the first ten days and then began to return to normal. The
depression of plasma cholesterol in all three dogs occurred earlier
and began to return to normal sooner than the rise in,p3apma APase
activity. The dog that received the highest dose offfl--lshowed the
greatest change in plasma APase from the pre-exposure--Bean. The
activity of a number of enzymes considered to be sensitive indi
cators of Uver injury was measured in the plasma when a 60 nig/kg
dose Gf[fiwas adffiitiisfcered. The results of these biochemical
measureAenw are presented in Table 7. All the plasma enzymes
measured were elevated
of 60 mg/kg of]|B|Rwas
within the first three days
administered. The greatest
after the
increases
dose were
in the OPT andWase. Within one week, all but these were within
the normal range. The depression of the plasma cholesterol
occurred more slowly, but there was no evidence of a return to
normal after three weeks as occurred in the dogs receiving 6 or
9 rog/kg.
With the 200 mg/kg dose of^ffUU the GPT and GOT were
elevated in both dogs within 48-TOurs? One week later, they were in the normal range. When 450 mg/kg of this compound was admin istered, all of the enzymes measured were markedly elevated 24 to 48 hours later. The greatest change occurred in the GPT and ICDH. Both animals expired within 48 hours after dosing.
The 450 mg/kg dose oflftaBB caused elevated levels of all
the enzymes measured withifr-w Hours in one (No. 2) of the two dogs exposed. On the tenth day after the dose was administered these were within the normal range. The other dog showed no effect from the treatment. At the 670 mg/kg dose of this compound,
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Dog No. 2 showed a rise in GOT, GPT, and APase during the first
48 hours, and a return to normal within two weeks. There was a slight rise in the APase, GPT and GOT in Dog No. 1.
SUMMARY
Single oral doses of 12 ng/kgof^--ga|dministered to rats, cause a rapid growth of the liver fchahrontinues for as long as two months after the treatment. Morphologically, the change is characterized by an enlargement of the hepatocyte. Changes in the biochemical composition, enzyme activity and respiration,
accompany this enlargement and indicate a disturbance in the normal metabolic functions of the organ. The changes in nucleic acid content and morphology of the cell suggest an interference in mitofcie activity. Reversal of these changes begins in two months and is nearly complete in five to six months.
Rats that have been subjected to excision of 60 to 1Q% of ner 48 hours before or after a single oral dose of 12 ag/kg ^regenerate larger than normal livers.
----11----------l?iB more toxic .foe, rats that have been
given^a single oral dose'of 12 mg/kg of|an|T^ls may result
from the accumulation and retention of cne^l----ln the enlarging
liver which has more fat and less glycogen Than normal liver.
When IM^ is administered to rats in a single dose of 12
mg/kg sImiHraneously with or after their exposure to repeated sublethal oral doses of ethyl alcohol, the increase in 3" weight observed is not any greater than that produced 03
alone at the same dose.
Following an Initial depressant effect byT----onenzymes
that metabolize sodium pentobarbltal, there is apparently an increase in the rate of metabolism of sodium pentobarbltal so
that it cannot exert its anesthetic action at usually anesthetic
dose levels.
Liver function studies in dogs have shown thatjw BHBB--|BB| dispersing agents affgctU.ie liver.
the liver. Doses oftfio-rog/kg ofiHH^SrSoO mg/kg of]
produce elevated plasma leyeig op-enzyme
of cellular damage. Only i|----(lowers the
activity ine
cholesterol
dogs given 4 mg or more per'-Bg of body weight in a single oral
dose. Of all the measurements made, alkaline phosphatase and
GPT are the most sensitive in detecting an effect on the liver
in dogs from all three dispersing agents.
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I EFFECT OF FLUOROCARBON DISPERSING AGENTS ON THE LIVERS OP RATS AND DOGS
II & 1 Report No. 123-65
I HASKELL LABORATORY FOR TOXICOLOGY I AND INDUSTRIAL MEDICINE
II Report by;
\y-^A/\ }C t-^a^yjt^,^ /\John R. Barnes
Chiej^ Biochemistry Section
9^^ '4^^^ I HHeennrryy^ Sherman Chief, Oral Toxicity Section
I
I
I JRB/HS/ah
I
S-^-^
I
I
I
I
Approved by;
Q'^^^M^L/^T^. / I'Sesley/Claytony 3,
' Asstslj^nt Dir^ctcy^
./
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.%
TAHL-E 1
Body Weight gm
Liver Weight gm Liver % Body
Oa ,fL/hr. COa / L/hr.
RQ
APase BU/gm
Esterase U/gm Choline Oxidase
Water % Protein % Fat % Glycogen % Ash %
Cholesterol % NPN % Phospholipids % Potassium % RNA %
DMA ^ Plasma APase BU
100 ml
Plasma Cholesterol mg^
BK)CHEMICA^. CHAtIQES IN RAT LIVISR
2-5 Weeks
Control <----\
545
15.5 3.94
524
28.3 8.80
2 Months
Control
546
&U- J 476
18.0 5.50
27,9 5.86
7.25 5.84 0.81
2.45
245 69
7.97 5.75 0.72
5.60
180 61
7.00 5.67 0.81
2.66
210 65
6.99 5.08 0.72
2.86
245 78
68.8 18.1 4.14 4.54 1.58
0.45 0.25 5.15 0.54 0.907 0.160
69.8 19.6 4.18 2.60 1.56
0.40 0.26 5.96 0.55 0.872 0.124
68.0 17.2 5.05 5.86 1.56
0.44 0.21 5.29 0.42 0.854 0.176
51
68.2 18.5 5.51 2.95 1.52
0.40 0.25 4.17 0.40 0.786 0.158
51
95
144
' 5 1/2 Contro
640
18.8 2.95
6.10 4.68 0.77
5.41
74
68.5 16.7 4.87 4.44 1.56
0.29
5.08 0.40
0.824 0.185
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TABLE 2
BIOCHEMICAL CHANG\:E&. ULRRAATT LIVER TISSUE 2 WEEKS AFTER HEP ATI
AND
TREATMENT WIT'HH' V^AND AFTER TREATMENT VJITHW--------
---^----
Treatment 1 Treatment 2
No.
of
1Rats
Mortal! by
Liveic
Weiglit
Liver
%
Body
CHy-
( sogen
APase
pnlo 11.p
^ 0
Hepatectomy
4
0
Sham Operated
6
0
W^^B Hepafcectomy
w
Hepatectomy
0
6
0
6
0
6
1/6
6
6/6
12.6
5.15 4.60 5.80 5
50.5
8.24 2.47 5.94 5
29.2
7.29 2.07 4.55 4
24.6
7.18 1.74 5.82 4
15.6
5.71 4.16 2.69 5
All animals died within 48 hours a
a) 12 mgji^g^kgbody weight
b) 0.1 ml\----pl00gm body weight
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TABLE?
Group
DOSING AND SACRIFICE SCHEDULE OP ANIMALS GIVEN
AND
------------1===---------==----C
Tc>tal No of
Ani.malt?
4 Hre After
10th Doee
Number of Ami.rnals Sacrificed
14 Days After
10th Dose
28 Days After
10th Dose
Control (no dosing)
8
2
2
2
^^ 8
2
2
2
T2250 nig/kg/day,
5 x week for 2 weeks)
3(2250 mg/kg/day,
6
2
2
jfeek for 2 weeks) +
Jf(12 nig/keen day of
E'irst ------ri^dose)
A (2250 mg/kg/day,
6
_ x week for 2 weeks) +
-- ^t--h^1--2m--g--/kgRdoons^dJaIy of
--------(2250mg/kg/day,
4
xweek for 2 weeks) +
|da^y(1af2temr g1/0ktgh<o--n--l--4t--t
tdos'*)
2
2
2
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TABLE 4
Group
LIVER WEIGHTS OF AIQ.MALS RECEIVING REPEATED DQSES
OFUI------k--iJAND A SINGLE DOSE off--iT
LJ.ver Weights (gin) of Animal a Sacrifice
4 Hrs. After 14 Days After 28 Days After
10th. Dose
10th Dose
10th Dose
Control
(no closing)
^w? l^2250 nig/kg/day, t? x week for 2 weeks) A(2250 mg/kg/day, ,week for 2 weeks) + rsit(^1f2l--m--g/^kRaodnosdea) y of 1(2250 mg/kg/day, ek for 2 weeks) + on day of dose)
-----(2250 nig/kg/day,
xweek ----(12
n
fo
ig/
r
k
g
2
Q
w
D
eeks)
l4th
+
fay after 10th
dose)
16; 15
^ -*
25; 50
16; 20 24; 19 42; 52
59; 44
19; 25 25; 21
56; 55 50; 41
* 1 animal died after the fourth dose
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TABLE 5
AVERAGE SLEEPING TIMES OP RATS GIVEN Na PENTOBARBITAL INTRAPERITONEALLY AT A DOSE LEVEL OF 30 ing/kg
Treatment Control
Pre -Expo sure 2^ Hours
PST 3& R 49 t 14 10 TCT
T
S
T
4
H_ou_r_8 S&
__ R
_
__
PS
_24_
T t
_H
o_u_rPs
S&
o
R
s
t
-
H o u r s b E xWp o s u r e _ _ _ _ _ _ _D_a_ys_--_
75T + SB R" PST t SB
52 + 8
10 $6 + 11 10 40 t 9
9
'
TO'
TO'
TO
47 + 6
10 121 + 14 10 56 + 8
7 25 + 6
8
s ) ' ' n T " T o ' ' ' mT O" T^ 'oT O ' T O Control
TCT'TO" 30+12 10 47 + 8
10 47 + 6
10 46+11
8 56 + 12
56 + 15 10 145 + 18 10 55 + 12
7 22 + 6
7
-
TO
T5
TC
"
-TO
PST + SD =
R
=
Average Pentobarbltal Sleeping Time + Standard Deviation (mi Number of rats which went to sleep
Total number of rats dosed
c^s.^.o.----------
Treatment
9 D)ays
PST f SD
TABLE 5 (Cont'd)
AVERAGE SLEEPING TIMES OF RATS GIVEN Na PENTOBARBITAL INTRAPERITONEALLY AT A DOSE LSVEL OF 30 nig/kg
16 Days
Post-Exp osure
27 Days
49 Days
56 Days
R
PST + SD
R
PST + SD
R
PST + SD
R
PST + SD
Control \
ten (12 mg^kg
Control
72 + 10
9 ^ + 18 IC8T 80+25
9 81+20 10 76 + 16 TO
^ JXg
0
(iSigTkg)
10
0
I(?
0 18+4
10-
^7 22 + b
P ST + 3D = Average Pentobartsital Sleeping Time + Standard Devi ation (minu R = Number cf rats vrt'ilch went to sleep Total number of rats dosed
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TABLE 6
CLINICAL AND BIOCHEMICAL OBSERVATIONS IN DOGS ADMINISTERED FLUOROCARBON DISPER
Compound
No. Dogs
Dose_^$_r__
nig/kg Rat ALP
6
10
Clinical
None
Mortality
0
Bi
Hypochole
APase
9 4 26
60
200 450
2
450
^ 2
670
15
None
0
7
None
45
None
100
Vomiting, anorexia,
O
polydlpsia, weakness,
wt. loss, black tarry
feces for 4 days
50
Vomiting, polydipsia
0
6'<
Vomiting, polydlpsia,
2
blood, feces and vomjtus,
tremors, convulsions, anorexia,death 1-5 days
50
Vomiting, 2-4 hours
0
45
Vomiting
0
Hypochole APase, BS
Hypochole
APase, BS
Hypochole APase, OP
Hypochol
APase, OP
lase. Jau
Elevated
(2/2), lo
Elevated LDH, aldo
Normal or
choleste
ICDH, LDH
Normal o
esterol,
(2/2),sl.
amylase a
vated aft
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TABLE 7
Dose
26*
Days
After
Dose O* 8
13 22 57
LIVER FUNCTION TESTS IN DOGS
Cholesterol
me %
13>5
66 49 47 86
APase
Bod. Units 2.5 5.5 5.5 7.5 7.2
GPT
Units
55
ic^l---l --
ICDH
Units
250
LDH
Units
130
5
74
7
78
60
10
64
14
50
21
48
21.7 15.7 15.4 15.1 11.4
850 270 155
91 77
5900 145
290 145
560 60 40
100
* Average pre-exposure
** Previously received 4 mg/kg 6l days before a dose of 26 nig/kg
Company Sanitized. D^es
TABLE 7 (Cont'd)
Dose
(nig/kg)
^ 3 n W t Csob--*
I w t --450*^
I<S-^5f01-7
&r--So--^7 670
Days
After
Dose
o*
1 2
J
7 12 , 21
27
i 2
0*
2 4
7 10
14.
22
2
4
?
7
12 21 27
2 1 2 1 2 1 2 1 Cholesfcerol nig % 1
101
112
102
95
109
111
126
126
106
112
100
127
92
109
89
106
APa ae
Bod. Units
GPT Units
2.8 1.7 42
56
2.6
2.1
58
50
2.6 6.9 56 845
2.5 10.1 108
425
1.8 8.0 56 166
1.4 5.4 40
70
1.8 5.7 56
44
2.4 5.5 42
40
GOT IJnlts
25
21
20
56
58
880
54
52
18
22
12
14
16
50
16
16
ICDH 1In
118
164 7.5 20.5 280 8500
145
58.7
8600
2100 1
112
112 1.2 2.4 25
55
14
16
15?
126
126
1.6
5.8
50
116
116
102
124
2.0
4.4
55
84
128
152 1.7 5.8
100
125 1.5 2.5 27
45
145
121
155 1.7 2.1
40
142
156 1.1 1.4
25
142
124 1.9 2.4 66
52
58
22
159
149
1.9
2.8
70
170
44
172
144
154
1.7
5.6
58
190
18
54
^
124
155
1.4
5.5
42
100
14
22
102
155
1.2
2.4
54
48
16
16
127
155
1.0
2.0
56
50
18
24
140
156
1.2
2.1
56
46
14
16
* Average pre-exposure
Compaq s^^.n------
I
I
FIGURE 1
I
LIVER WEIGHTS OF RATS RECEIVING A SINGLE ORAL DOSE
112in/kg)MB]
I
<i_
^
^r *j
I
I
I
I
I
I
oi--ii
ososo3 --i--i--i--i--i TIME IN
5SoTio i i--i--i--,' DAYS
i
'
s
'
o
I FIGURE 2 PLASMA CHOLESTEROL OF DOGS RECEIVING
I
ORAL DOSES WJffJ
I
----NEAN (Lr^MMIIJU. IUNC
I
I
I
I
I
I
^^.^^y^'^>*.^*^*^"-*^^>.''7^^^*">^^'^f>^f.*^T'*<^K*^*\^^ff"'.^^f*f^';"^^'*"^^'*^"*-1'^^^^^^^
;^';.^\^\c^;.^
g^^^i^^^^^^
I^^^^^^^^^^^^^^^^^^^^^^^^^^^B
^^^^^^^^^^^^^^^^^^^^^^^^^^^B"
I I
\ / \ ^ :"y-:<">:":"^:"a^^iY;-^~^^^^^^
{f^--itim^,
FIGURE 3
PLASMA ALKALINE PHOSPHATASE 0F DOGS
RECEIVING ORAL DOSES
MEAN
(''"-'^i NORMAL RANGE
w
^
DAYS
<o
0,
8
