FUNDAMENTAL AND APPLIED TOXICOLOGY 20. 34 I -347 ( 1 99? )
Acute Methanol Toxicity in Minipigs1
DAVIDC. DORMAN.* JANICE A. DvE.t MARK. P NASSISE.J JETIIRO HKL r v* BRAD BOLON.* AND MICHELE A. MEDINSKY
'Chemical Imlimirv ln\iitiili'nl Ti>yiiiittn>vcincl^lli'tilili l:'lli-ti\ Kwiiri It l.,ih< ir,u,l I'cit-rniun l/n//i/ur Vnr//i i .ii<-/ni,i s/i//, ( /jni'/w/t. RiiU-iaii. \i>rili Citroltiiii .'
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Received August :?. |iW2; javpk'd IVivmhcr : I.
Acute Methanol Toxicity in Minipigs. DORMAN. D. C. DVE.
J. A.. NASSISE, M. P., EKUTA. J.. BOLON. B.. AND MEDINSK\ .
M. A. (1993). Fundant. Appl. Toxicol. 20. 341-3-47.
:-; _The pig has been proposed as a potential animal model for
methanol-induced neuro-ocular toxicosis in humans because of
its low liver tetrahydrofolate levels and slower rate of formate
metabolism compared to those of humans. To examine the valid-
ity of this animal model. 12 4-month-old female minipigs (mini-
pig YU) were given a single oral dose of water or methanol at
1.0. 2.5. or 5.0 g/kg body wt by gavage (n = 3 pigs/dose). Dose-
dependent signs of acute methanol intoxication, which included
mild CNS depression, tremors, ataxia. and recumbency, devel-
oped within 0.5 to 2.0 hr. and resolved by 52 hr.'-Average maxi-
mum methanol concentrations in plasma, of 3100 ± 700 (SD).
6200 ± 2300. and 15.200 ± 900 Mg/ml were reached within 0.5
to 4 hr following methanol administration in animals given 1.0.
2.5. or 5.0 g methanol/kg, respectively. The mean initial elimina-
tion half-lives of methanol were 9.0 ± 1.6. 22.4 + 6.1. and 18.9
± 4.3 hr, for 1, 2.5. and 5.0 g/kg doses, respectively. In 3 mini-
pigs, a transient increase in plasma formate concentration
(1.74-3.40 mEq/liter vs control = 0.5 ± 0.3 mEq/liter) occurred
4 to 30 hr following methanol administration. Methanol- and
formate-dosed pigs did not develop optic nerve lesions, lexico-
logically significant formate accumulation, or metabolic acido-
sis. Based on results following a single dose, female minipigs do
not appear to be overtly sensitive to methanol and thus may not
be a suitable animal model for acute methanol-induced neuro-
ocular tOXicOSIS.^ ic 1993 Society ofToxicolog).
Methanol exposure may result in neurobehavjoral (In-
furna and Weiss. 1986). teratological (Infurna and Weiss.
1986: Nelson et a/., 1985). neurodevelopmental (Nelson et
a/.. 1985). reproductive (Cooper el a/.. 1992), and neuro-
ocular effects. The toxicity of methanol in humans is char-
acterized by central nervous system depression, weakness.
headache, vomiting, severe metabolic acidosis (McMartin
' This paper has been reviewed by the Health Effects Research Labora-
tory. U.S. Environmental Protection Agency, and approved for publica-
tion. Approval does not signify that the contents necessarily reflect the
views and policies of the Agency nor does mention of trade names or
commercial products constitute endorsement or recommendation for use.
ci nl.. I'M): Cljy ci a/.. 1975). optic disc edema (Hayreh ci
al. 1977). and hilaieral necrosis ot'lhc putamcn (Koopmans
citil.. I9S.X; LeyandGali. 1983: Sharpe cv
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342
DORMAN ET AL.
rats. Like humans, young swine and micropigs have low
hepatic tetrahydrofolate concentrations and appear to me-
tabolize formate at a rate slower than that observed in rats
(Makar el al.. 1990; Tephly el al, 1992).
It is predicted that the proposed heavier reliance on meth-
anol-based automotive fuels will result in an increased inci-
dence of blindness and deaths in people resulting from acci-
dental methanol ingestion (Litovitz, 1988). The animal
models available to study methanol-induced neuro-ocular
toxicity have been limited to nonhuman primates (Martin-
Amat el al., 1977) and to monkeys and rodents made fo-
late-deficient by nutritional or pharmacologic manipula-
tion (McMartin el al, 1977: Eells, 1991). Pigs represent an
attractive animal model for the study of methanol-induced
neurotoxicity. It would be predicted that pigs would accu-
mulate formate following methanol exposure based upon
their reported low levels of hepatic tetrahydrofolate con-
centrations and slow rate of formate metabolism (Makar el
al. 1990; Tephly el al, 1992). The actual sensitivity of
swine to methanol and methanol-induced neuro-ocular tox-
icity is unknown. This study was, therefore, performed to
evaluate the Yucatan minipig as a potential nonprimate
model for methanol neuro-ocular toxicosis by exploring the
toxicity and pharmacokinetics of melhanol and formate in
these animals.
MATERIALS AND METHODS
Chemicals. Methanol (high-performance liquid chromatograpny
grade) was obtained from Sigma Chemical Co. (St. Louis. MO). Sodium
penlobarbital was purchased from Abbott Laboratories (North Chicago.
IL). ketamine hydrochloride from Aveco (Fort Dodge. IA), halothane
from Fort Dodge Laboratories (Fort Dodge. IA), and tropicamide from
Alcon Laboratories (Ft. Worth. TX). Formate dehydrogenase was pur-
chased from Boehringer Mannheim Corp. (Indianapolis. IN). Hog kidney
acetone powder and all other chemicals were purchased from Sigma and
were of the highest available purity.
Animals. Fourteen. 4-month-old. 8.5 to 13.0 kg, female minipigs
(Minipig YU. Charles Rivers Breeding Laboratories, Wilmington, MA)
were used. Minipigs were housed individually in raised stainless-steel runs
with tenderfoot flooring. They were fed a commercially available, pelleted,
pig and sow diet (Wayne Feed Division, Chicago, IL) meeting National
Research Council nutritional specifications for swine. Food and water
were available ad IMium except for the 12 hr immediately prior to surgery
or methanol administration. A 12-hr light/dark cycle was provided
throughout the study.
Catheter implantation. Following premedication with atropine (0.04
mg/kg. sc). ketamine (10 mgAg, im), and xylazine (5 mg/kg, im), anes-
thetic induction was achieved with 1.5 to 2.0% halothane. Animals were
maintained on I to 1.5% halothane in a closed circuit system. External
jugular vein and carotid artery catheters were surgically implanted approxi-
mately 48 hr prior to methanol or formate administration using the meth-
ods described by Smith and coworkers (1989). A 75-cm long, single lumen,
medical-grade silicone elastomere tube (Silastic. Dow Coming. Midland,
MI) with an outside diameter of 2.2 mm and an inside diameter of 1.0 mm
was used for all catheierizations. Catheters were exteriorized through a
dorsal skin incision and placed into a vinyl pouch sutured to the skin
(Wittry et al.. 1990).
Melhanol administration. A single oral dose of melhanol (20% v/\ in
sterile water) was given by gavage at 0. 1.0, 2.5. or 5.0 g/kg (n = 3 pigs per
dose). Conirol animals were given a volume of water equivalent to the
highest volume given to the methanol-dosed group.
Formate administration. To examine whether formate accumulation
alone would result in neuro-ocular toxicosis, a formate buffer (sodium
formaie.formic acid. 10:1. 0.5 M, pH 7.4) was given (425 mg formate/kg)
intravenously every 4 hr for 32 hr to two additional minipigs. The dose of
formate gi\cn was anticipated to produce blood formaic concentrations
similar to ihose seen in formate-poisoned monkeys lhai subsequently de-
veloped neuro-ocular loxicity (Martm-Amal el a/.. 1978).
Animal monitoring and assessment of toxicity. Before and each 24 hr
after methanol dosing, funduscopic examinations were performed by indi-
rect ophthalmoscopy after inducing pharmacologic mydriasis with topical
tropicamide. In some pigs, retinal vascular permeability was also assessed
24 10 96 hr after melhanol administration by conventional fluoresccin
angiography (Bellhom. 1973). Angiographic hndmgs were recovered on
high-speed color film using a hand-held fundus camera (Kowa RC 2.
Kowa. Japan). Animals were monitored continuously for the development
of clinical signs during the first 8 hr after methanol or formate administra-
tion. They were subsequently observed for clinical signs at least every 4 hr
for the first 48 hr after dosing and then every 8 hr until completion of the
study. Serial neurologic and physical examinations were performed more
frequently in animals that developed clinical signs.
Blood gas analysis. Routine arterial blood gas analyses were per-
formed every 6 hr after melhanol administration using a commercially
available blood gas analyzer (IL 1306. Instrumentation Laboratories. Lex-
ington. MS).
Methanol and formate pharmacokinetics. Heparinized venous blood
(1 ml) was collected at 0.0.25,0.5. I, 1.5,2.4.8. 12. 16, 32. and 64 hr after
administration of melhanol or formate. All samples were kept frozen until
analyzed- Blood methanol concentration was determined by gas chroma-
tography-flame lonizalion detection using the meihods described by Pol-
lack and Kawagoe(199l). A Hewlett-Packard 5880A gas chromatograph
(Kennett Square. PA) equipped with a 30 m x 0.25 mm column (J&W
DB-Wax. J&W Scientific. Folsom. CA) and a I m x 0.53 mm deactivated
silica precolumn were used. Temperatures were as follows: injector. 70°C:
detector, 325°C; column oven, I05°C. These conditions produced reten-
tion times of 1.9 and 2.1 mm for acetonitriie (external standard) and metha-
nol. respectively. Blood formate concentration wasdeterminedspectropho-
tometrically using the enzymatic method of Cook el al. (1991).
Liver (total) folate determination. Liver samples from control pigs
were prepared as described by McMartin and coworkers (1981). Folates
were assayed in their monoglutamate form after hydrolysis with hog kid-
ney polyglutamate hydrolase prepared from hog kidney acetone powder
(Lin and Lester. 1985). Total hepatic folate was determined using a com-
mercially available homogenous enzyme immunoassay (Microgenics Cor-
poration, Concord. CA) described by KJianna and coworkers (1989).
Pathology. Animals were euthanatized 10 days after melhanol admin-
istration. Minipigs were tranquilized with chlorpromazine (0.3 mg/kg. iv)
and anesthetized by the intravenous administration of pentobarbital (20.0
mg/kg). Following induction of deep anesthesia, a liver biopsy specimen
was obtained from control minipigs through abdominal laparotomy. The
liver wedge was frozen in liquid nitrogen and stored at -80°C until ana-
lyzed for folate. The aorta was then cannulated through the left ventricle
with a 13-mm o.d. plastic catheter, and 2 liters of 0.9% saline containing
2000 IU heparin/liter at a temperature of 37°C were infused through the
catheter by gravity at a pressure equivalent to 120-150 mm water. Blood
and saline escaped from the vascular system through a 2- to 3-cm incision
in the right auricle. When the escaping saline became clear, the infusion
was changed to 2.5% glutaraJdehyde in 0.1 M phosphate buffer (pH 7.4).
also at 37 "C Each pig was perfused with 4.0 liters of this fixative. The total
fixative perfusion time ranged from 20 to 35 min.
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METHANOL TOXICITY IN MINIPIGS
343
A necropsy was performed immediately on each fixed animal. The fol-
lowing tissues were collected for histologic examination: brain (cerebrum.
cerebellum, and brain stem), spinal cord (cervical and lumbar intumes-
cences), eye (optic nerve and retina), kidney, liver, lung, heart, adrenal.
pancreas, and spleen. Tissues were stored overnight in 2.5ri< glularaldchyde
in 0.035 M phosphate buffer (pH 7.4) at 4°C. processed by standard proce-
dures, embedded in paraffin, sectioned at 5 ^m. and stained with hemato\-
ylin and eosin.
Data analysis. Because of the small sample size (/i = 3 per dose group).
no formal statistical analysis was performed. Data are reported js means
± SD. Peak plasma concentration (Cml.) and time to peak plasma concen-
tration (/„„) were determined by inspection of the methanol plasma con-
centration vs time results. The half-life ((l/:) of melhanol was estimated
from the slope of the terminal phase of the log plasma conccniration-ume
plot tilted by the method of least squares. Following the initial intravenous
dose of formate, the 1II3 of formate was estimated from the slope of i he log
plasma concentration-lime plot and was also fitted by the method of least
squares.
RESULTS
Clinical signs of acute toxicosis developed within 0.5 to 2
hr of methanol administration and resolved by 52 hr. The
clinical signs of methanol toxicosis included mild to severe
CNS depression (8 of 9 pigs), ataxia (8/9). recumbency (2/
9). and tremors (1/9). Once they had recovered from the
initial effects, the minipigs remained asymptomatic until
they were euthanized. With each increasing methanol dose.
the time until the onset of clinical signs decreased, and the
duration and severity of clinical effects increased. No clini-
cal signs were apparent in the control minipigs given water.
Clinical signs consistent with ocular toxicity were not ob-
served in any of the minipigs given methanol. Their pupil-
lary light reflexes and menace responses remained normal.
and the pigs appeared to maintain the ability to negotiate
around objects. No significant changes in the optic nerves
and retinal vessels were observed using funduscopic exami-
nation or fluorescein retinal angiography. The 10-day histo-
logic evaluation of one of the minipigs given the highest
methanol dose (5.0 g/kg) revealed multifocal degeneration
of the outer retinal layers (Fig. I). The accumulation of
amorphous cellular debris in the outer nuclear layer re-
sulted in the elevation of the adjacent sensory retina. How-
ever, no histopathologic lesions consistent with methanol-
related toxicosis were seen in the eyes of other methanol-
treated or control minipigs. Putamen lesions were not
observed in brain cross-sections from either methanol-
treated or control minipigs.
A dose-dependent increase in blood methanol concentra-
tion was observed. Mean peak plasma methanol concentra-
tions (±SD) of 3100 ± 700. 6200 ± 2300, and 15,200 ± 900
Mg/ml occurred 0.5 to 4 hr after administration of 1.0. 2.5,
or 5.0 g methanol/kg, respectively (Fig. 2). The mean initial
elimination tl/2 of methanol was 9.0 ± 1.6, 22.4 ±6.1, and
18.9 ± 4.3 hr for animals given 1.0, 2.5, or 5.0 g methanol/
kg, respectively. The terminal phase elimination ?I/2 of
methanol could not be determined.
Although a slight decrease in blood pH was noted in the
minipigs given 5.0 g/kg methanol (Fig. 3). neither depletion
of blood bicarbonate nor formic acidemia occurred. In
three of the minipigs (from the I and 2.5 g/kg dose groups).
a transient, dose-independent increase in plasma formate
concentration (1.74-3.40 mEq/liter) developed between 4
and 30 hr after melhanol gavage (Fig. 4): endogenous blood
formate concentrations in control minipigs were 0.53 ±0.3
mEq/liier.
Minipigs given intravenous formate developed depres-
sion, polyuria. and polydipsia between 36 and 40 hr after
the initial formate dose. Neither animal given formate de-
veloped metabolic acidosis or significant formate accumu-
lation (data not shown). Minipigs given formate had nor-
mal pupillary light reflexes and menace responses and did
not develop clinical signs consistent with optic nerve or
retinal involvement. No significant changes in the optic
nerves and retinal vessels were observed using funduscopic
examination or fluorescein retinal angiography. No histo-
pathologic lesions consistent with formate-related toxicosis
were seen in the eyes of minipigs given formate. The initial
formate elimination /,/2 was 50 and 1 12 min for the two
minipigs given formate intravenously (Fig. 5).
The average total hepatic folate concentration in the con-
trol minipigs was 17.5 ± 2.2 nmol/g of liver (n = 3).
DISCUSSION
The use of the pig as an animal model of methanol poi-
soning in man has been suggested by Makar and coworkers
(1990). They based their hypothesis on the known associa-
tion between formate accumulation and the subsequent de-
velopment of metabolic acidosis and blindness in species
sensitive to methanol poisoning. Formate is converted by
10-formyltetrahydrofolate synthetase to 10-formyltetrahy-
drofolate. 10-Formyltetrahydrofolate is subsequently me-
tabolized by 10-formyltetrahydrofolate dehydrogenase to
carbon dioxide (Johlin el al.. 1989). The rate of formate
metabolism, therefore, is dependent on adequate levels of
hepatic folic acid, especially its tetrahydrofolate form (Joh-
lin el al., 1987). As demonstrated by Makar and coworkers
(1990), some pigs have low liver tetrahydrofolate concen-
trations and a decreased rate of formate metabolism, sug-
gesting an increased sensitivity to methanol toxicosis. In
our study, however, a single oral dose of 1.0 to 5.0 g/kg of
methanol failed to result in formate accumulation suffi-
cient to induce toxicity. The dose at which methanol-in-
duced neuro-ocular toxicity occurs in pigs remains un-
known. The doses of methanol used in this study are compa-
rable to or greater than the minimal lethal oral dose (1.0
gram/kg) of methanol in humans (Roe. 1982). There are a
number of cases in which adult humans have survived the
ingestion of 500 to 600 ml of methanol (Naraqi el al.
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344
DORMAN ET AL.
FIG. I. Multifocal reiinal degeneration ofihe outer retinal layers (b) in a mmipig given methanol (5.0g/kg) 10 days earlier, compared to control (a).
Accumulation of amorphous cellular debris (arrow) in the outer nuclear layer resulting in the elevation of the adjacent sensory retina is also present. (HE.
40x).
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METHANOL TOXICITY IN MINIP1GS
345
12 24 36
Time after dosing (hrs)
48
FIG. 2. Blood methanol concentration following a single oral dost of
methanol (n = 3 minipigs per dose). Error bars (.v ± SD) nol visible arc
within the symbol used.
1979). Even among sensitive humans, there is a tremen-
dous amount of variability in the methanol dose-response.
The oral absorption and total body clearance of metha-
nol in these minipigs appeared similar to those observed in
humans. Whether unusual methanol distribution or metab-
olism occurs in minipigs is unknown. Minipigs rapidly ab-
sorbed the methanol and developed maximal blood metha-
nol concentrations (range, 1600 to 30,300 Mg/ml) that were
comparable to those reported in humans following metha-
nol ingestion. These plasma methanol concentrations ap-
pear higher than what would be expected based on metha-
nol kinetics in other species. Although maximal blood
methanol concentrations following acute lethal methanol
exposure in humans are often undetermined, blood metha-
nol levels in excess of 1000 ^g/ml are commonly reported
within 24 to 48 hr of methanol ingestion (Jacobsen et al.,
1982: Naraqi et al.. 1979; Kane et al., 1968; Swartz el al..
1981). The initial methanol elimination half-lives (9 to 22
hr) observed in the minipig were also comparable to those
7.7-,
7.2
24 36 48 60
Time after dosing (hrs)
12 24 36 '& 50 72
Time after melhanol administralion (nr)
FIG. 4. Individual animal blood formate concentrations following a
single oral dose of methanol. Only three minipigs. two from the lowest (1.0
g/kgl and one from the intermediate (2.5 g/kgl melhanol dose groups, had
increased blood formate levels following methanol administration. All
other minipigs did not have increased blood formate concentrations, in-
cluding three minipigs given 5.0 g melhanol/kg and the remaining animal
from each of the lower 11 or 2.5 g/kg) methanol dose groups.
reported following methanol ingestion in humans (17 to 27
hr) without ethanol or dialysis treatment (Kane el al..
1968). Finally, as in humans, methanol administration was
associated with transient CNS depression and aiaxia that
paralleled their blood methanol concentrations.
Ultimately, however, no significant accumulation of for-
mate occurred in any of the methanol-treated minipigs in
this study. Blood formate levels in excess of 10 mEq/liter
are reported in humans with neuro-ocular toxicosis follow-
ing methanol ingestion (Sejersted et al., 1983: McMartin et
al.. 1980). Although there was a mild decrease in the blood
pH of the minipigs given the highest methanol dose (5 g/
kg), none of the methanol-treated minipigs developed a de-
gree of metabolic acidosis or bicarbonate depletion consis-
tent with methanol poisoning in humans. Minipigs in this
study given the highest methanol dose (5 g/kg) had blood
bicarbonate levels 72 hr after methanol ingestion (25.5
100,
0.1
30 60 90 120 150 190 210 240
Time (min)
FIG. 3. Blood pH following a single oral dose of methanol (n
minipigs per dose).
FIG. 5. Initial formate elimination following an intravenous adminis-
tration of buffered formate (425 mg/kg) in two minipigs.
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346
DORMAN ET AL.
± 1.5 mEq/liter) that were similar to those of control mini-
pigs (27.8 ± 1.4 mEq/liter). For comparison, a blood pH
less than 7.2 with a blood bicarbonate concentration less
than 15 mmol/liter commonly occurs in methanol-poi-
soned humans with blurred vision (Jacobsen el al.. 1982:
Sejersted a al.. 1983). The significance of this decrease in
blood pH in the highest dose group of pigs in the present
study is unknown.
Susceptible species have lower total liver folate concen-
trations and slower formate metabolism, and thus in-
creased sensitivity to methanol when compared to resistant
species such as rats. For example, total liver folate concen-
tration in humans (15.8 ± 0.8 nmol folate/g of liver) and
monkeys (25.5 ± 1.2 nmol folate/g of liver) are lower than
those observed in rats (25.3 ± 0.9 nmol folate/g of liver) and
mice (60.9 - 2.1 nmol folate/g of liver) (Johlin el al.. 1987).
Previously reported values (5.1 ± 1.2 nmpl/g of liver) for
total liver folate concentration in young swine (Makar ei
al.. 1990) and micropigs (8.2 ± 0.6 nmol/g of liver; Tephly
ci al.. 1992) were lower (17.5 ± 2.2 nmol/g of liver) than
those determined for control minipigs used in this study.
These findings are consistent with the lack of formate accu-
mulation observed in the minipigs. However, even within
this strain of minipig. formate elimination was variable. In
this present study, one minipig given formate directly had
an initial rate of formate elimination (/,/: = 50 min) that
was similar to that reported for rats (Johlin ei al.. 1987).
while a second minipig had a much slower initial rate of
formate elimination (/,/2 = 112 mm) similar to that re-
ported for young female swine (/,/2 = 87 ± 18 min; Makar et
al.. 1990) and micropigs (/,/2 = 74.1 ± 6.0 min: Tephly et
al.. 1992). Humans have low (15.8 ± 0.8 nmol/g of liver)
total liver folate concentrations (Johlin et al.. 1987) that
result in slow formate elimination, but this elimination rate
of formate in humans is also variable (tl/2 = 60 to 120 min:
McMartin ct al.. 1980). These results suggest that strain
differences as well as differences between individual ani-
mals in formate metabolism may exist.
Most importantly, none of the minipigs given methanol
developed clinical signs of ocular toxicity. although one
minipig given the highest methanol dose (5 g/kg) did have
histopathologic evidence of multifocal retinal degenera-
tion. Histopathologic evidence of retinal damage following
methanol administration has been reported in nitrous ox-
ide-treated methanol-exposed rats (Murray et al.. 1991).
Electroretinographic alterations suggestive of retinal in-
volvement have also been reported following methanol ad-
ministration to mice (Carricaburu et al.. 1979). monkeys
(Potts ei al.. 1955). and folate-deficient rats (Eells, 1991).
Interestingly, in this study, retinal degeneration in this mini-
pig developed in the absence of significant formate accu-
mulation (maximal blood formate = 1.8 mEq/liter). These
results, albeit limited, suggest that methanol may be acting
as a direct retinal toxicant or. alternatively, that regional
(ocular) methanol metabolism to formate occurs at a rate
sufficient to induce retinal toxicity. Whether formate in vit-
reous humor accumulated to toxic levels in this animal is
unknown. However, vitreal accumulation (in excess of
blood concentrations) of formate has been reported in rats
(Eclls. 1991). It is possible that similar lesions may have
been present al earlier times in the other methanol-treated
minipigs. However, no microscopic evidence of retinal dam-
age or repair was observed.
Since acute methanol-induced neuro-ocular toxicosis of-
ten develops in humans following a single oral ingestion of
methanol (>0.4 to I g/kg). it does not appear that the Yuca-
tan minipig on a normal folate diet will serve as a suffi-
ciently sensitive animal model to study this syndrome or to
evaluate effective means of therapeutic intervention. Simi-
larly, rhesus monkeys given a single oral dose (0.5 to 6.0
g/kg) of methanol comparable to those given to the mini-
pigs used in this study survived (Cooper and Felig, 1961).
As with other animal models including primates (Martin-
Amat et a!.. 1977). it is still possible that the administration
of repealed doses of methanol to minipigs could result in
sufficient formate accumulation to result in neuro-ocular
toxicity.
ACKNOWLEDGMENT
We lhank Susan Brink for technical assistance throughout ihis project.
We also thank Dr. Charles McPherson and the North Carolina State Uni-
versity College of Veterinary Medicine's Lab Animal Resources staff for
the use of their facilities and their assistance with ihis project, Research
supported in pan by NRSA ES05558 (DCD).
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MS-92-219
TECHNICAL REPORT DATA
fPiease read/nstructfws on the nyffse before c&npietmgj
. REPORT NO.
EPA/600/J-94/392
2.
3. RECIPI
PB95-126520
4. TITLE AND SUBTITLE
ACUTE METHANOL TOXICITY IN MINIPIGS
5. REPORT DATE
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
J.A. Dye,1 D.C. Dormcn,2 M.P. Nassise,3 J. Ekuta,-2 B. Bolon,2 M Medinsky2
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
'EPA.HERL.ETD.PTB, RTP, NC 27711; 2CIIT, RTP, NC 27709; 3Coll. Vet. Med., NCSU,
Raleigh, NC.
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
OFFICE OF RESEARCH AND DEVELOPMENT, U.S. ENVIRONMENTAL PROTECTION AGENCY,
HEALTH EFFECTS RESEARCH LABORATORY, ENVIRONMENTAL TOXICOLOGY DIVISION,
PULMONARY TOXICOLOGY BRANCH, RESEARCH TRIANGLE PARK, NC 27711.
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA-600/10
15. SUPPLEMENTARY NOTES
Fundamental and Applied Toxicology
20(3): 341-347, March 1993
16. ABSTRACT
The pig has been proposed as a potential animal model for methanol-induced neuro-ocular toxicosis in humans because
of its reported low liver tetrahydro folate levels and therefore, slower formate metabolism as compared to humans. To determine
the validity of the animal model, rninipigs were given a single oral dose of methanol or water. Dose-dependent signs developed
including mild CNS depression, tremers, and ataxia, however, these subjects failed to develop optic nerve lesions, toxicologically-
significant formate accumulation or metabolic acidosis. Methanol and formate pharmocokinetics are also discussed.
17.
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RELEASE.TO THE PUBLIC
19. SECURITY CLASS (Mis Report}
Unclassified
21. NO. OF PAGES
7
20. SECURITY CLASS (Thapoge}
Unclassified
22. PRICE
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