Addendum to the March 2011 External Peer Review Draft IRIS Toxicological
Review of Methanol (Non-Cancer) (EPA/635/R-11/001)
(June 16, 2011)
Note to peer reviewers: The text below highlighted in red underline includes revisions made to
the Methanol (Noncancer) Toxicological Review subsequent to its release for public comment.
The bracketed green text provides orientation as to the placement of the text within the
toxicological review. These revisions were made to incorporate recently published literature.
3.1. OVERVIEW
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The primary route of methanol elimination in mammals is through a series of oxidation
reactions that form formaldehyde, formate, and carbon dioxide (Figure 3-1). As noted in
Figure 3-1, methanol is converted to formaldehyde by alcohol dehydrogenase-1 (ADH1) in
primates and by catalase (CAT) and ADH1 in rodents. Although the first step of metabolism
occurs through different pathways in rodents and nonhuman primates, Kavet and Nauss (1990)
report that the reaction proceeds at similar rates (Vmax= 30 and 48 mg/h/kg in rats and nonhuman
primates, respectively). In addition to enzymatic metabolism, methanol can react with hydroxyl
radicals to spontaneously yield formaldehyde (Harris et al.. 2003). Mannering et al. (1969) also
reported a similar rate of methanol metabolism in rats and monkeys, with 10 and 14% of a 1 g/kg
dose oxidized in 4 hours, respectively; the rate of oxidation by mice was about twice as fast, 25%
in 4 hours. In an HEI study by Pollack and Brouwer (1996). the metabolism of methanol was
2 times as fast in mice versus rats, with a Vmax for elimination of 117 and 60.7 mg/h/kg,
respectively. Despite the faster elimination rate of methanol in mice versus rats, mice
consistently exhibited higher blood methanol levels than rats when inhaling equivalent methanol
concentrations (See Tables 3-4 and 3-5). Possible explanations for the higher methanol
accumulation in mice include faster respiration (inhalation rate/body weight) and increased
fraction of absorption by the mouse (Perkins et al.. 1995a). Sweeting et al. (2010) examined
methanol dosimetry in CD-I mice. New Zealand white (NZW) rabbits, and cynomolgus
monkeys, and found that peak plasma concentrations are not significantly different, but clearance
in rabbits is approximately half that of mice following a single 0.5 or 2 g/kg ip injection. This
suggests that rabbit clearance is similar to that in rats and monkeys, since Mannering et al.
(1969) found that rat and monkey clearance rates are also about half that in mice. Sweeting et al.
(2010) did not report the clearance rates from monkeys, but the 6-hour AUC in monkeys was
similar to that in rabbits. Because smaller species generally have faster breathing rates than
larger species, humans would be expected to absorb methanol via inhalation more slowly than
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rats or mice inhaling equivalent concentrations. If humans eliminate methanol at a comparable
rate to rats and mice, then humans would also be expected to accumulate less methanol than
those smaller species. However, if humans eliminate methanol more slowly than rats and mice,
such that the ratio of absorption to elimination stays the same, then humans would be expected to
accumulate methanol to the same internal concentration but to take longer to reach that
concentration.
In all species, formaldehyde is rapidly converted to formate, with the half-life for
formaldehyde being ~1 minute. Formaldehyde is oxidized to formate by two metabolic
pathways (Teng et al.. 2001). The first pathway (not shown in Figure 3-1) involves conversion
of free formaldehyde to formate by the so-called low-affinity pathway (affinity = 1/Km =
0.002/|jM) mitochondrial aldehyde dehydrogenase-2 (ALDH2). The second pathway
(Figure 3-1) involves a two-enzyme system that converts glutathione-conjugated formaldehyde
CY-hydroxy methyl glutathione [HMGSH]) to the intermediate »Y-formyl glutathione, which is
subsequently metabolized to formate and glutathione (GSH) by »Y-formyl glutathione hydrolase.1
The first enzyme in this pathway, formaldehyde dehydrogenase-3 (ADH3), is rate limiting, and
the affinity of HMGSH for ADH3 (affinity = 1/Km = 0.15/|jM) is about a 100-fold higher than
that of free formaldehyde for ALDH2. In addition to the requirement of GSH for ADH3 activity,
oxidation by ADH3 is nicotinamide adenine dinucleotide- (NAD+-)dependent. Under normal
physiological conditions NAD+ levels are about two orders of magnitude higher than NADH,
and intracellular GSH levels (mM range) are often high enough to rapidly scavenge
formaldehyde (Meister& Anderson. 1983; Svensson et al.. 1999); thus, the oxidation of
HMGSH is favorable. In addition, genetic ablation of ADH3 results in increased formaldehyde
toxicity (Deltour et al.. 1999). These data indicate that ADH3 is likely to be the predominant
enzyme responsible for formaldehyde oxidation at physiologically relevant concentrations,
whereas ALDHs likely contribute to formaldehyde elimination at higher concentrations (Dicker
& Cedebaum. 1986).
1 Other enzymatic pathways for the oxidation of formaldehyde have been identified in other organisms, but this is
the pathway that is recognized as being present in humans (Caspi et al., 2006: http://metacvc.org).
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Primates
Alcohol dehydrogenase
(ADHI)
CH3OH
(Methanol)
I
HCHO
(Formaldehyde)
Rodents
C'atalase (CAT)
and ADHI
j( + GSH)
Formaldehyde dehydrogenase
(ADH3)
Formaldehyde dehydrogenase
(ADH3)
j(-GSH)
S-formylglutathione hydrolase
S-formy(glutathione hydrolase
CAT-pero\ide and
Folate-dependent pathway
(see Figure 3-2)
Folate-dependent pathway
(see Figure 3-2)
H.MGSH
(hydroxymethyl-GSH)
(S-formyl glutathione)
HCOO (Formate)
C02 (Carbon dioxide)
Figure 3-1. Methanol metabolism and key metabolic enzymes in primates and rodents.
Source: IPCS (19971
Rodents convert formate to carbon dioxide (CO2) through a folate-dependent enzyme
system and a CAT-peroxide system (Dikalova et al.. 2001). Formate can undergo adenosine
triphosphate- (ATP-) dependent addition to tetrahydrofolate (THF), which can carry either one or
two one-carbon groups. Formate can conjugate with THF to form V°-formyl-THF and its
isomer N5-formyl-THF, both of which can be converted to N5, A'-methenyl-THF and
subsequently to other derivatives that are ultimately incorporated into DNA and proteins via
biosynthetic pathways (Figure 3-2). There is also evidence that formate generates CO2" radicals,
and can be metabolized to CO2 via CAT and via the oxidation of A'10-formyl-THF (Dikalova et
al.. 2001).
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Cytoplasm
Mitochondria
PURINES
10-formylTHF C
MTHFDI
FDH If
methenylTHF
formates ^ formate.
methenylTHF
THF
THF
cSHMT
serine
serine
dTMP
methyleneTHF
MTHFR
glycine
methyleneTHF S'>'clne
5-methyITHF
MS^"
homocysteine
Methionine
AdoHyc
AdoMct
Figure3-2. Folate-dependent formate metabolism. Tetrahydrofolate (T H F)-
mediated one carbon metabolism is required for the synthesis of purines,
thymidylate, and methionine.
Source: Montserrat et al. (2006).
Unlike rodents, formate metabolism in primates occurs solely through a folate-dependent
pathway. Black et al. (1985) reported that hepatic THF levels in monkeys are 60% of that in
rats, and that primates are far less efficient in clearing formate than are rats and dogs. Studies of
human subjects involving [14C]formate suggest that -80% is exhaled as 14CC>2, 2-7% is excreted
in the urine, and -10% undergoes metabolic incorporation (Hanzlik et al.. 2005. and references
therein). Sweeting et al. (2010) have reported that formic acid accumulation in primates within 6
hours of a 2 g/kg ip exposure to methanol was 5-fold and 43-fold higher than in rabbits and mice,
respectively. Mice deficient in formyl-THF dehydrogenase exhibit no change in LD50 (via
intraperitoneal [i.p.]) for methanol or in oxidation of high doses of formate. Thus it has been
suggested that rodents efficiently clear formate via high capacity folate-dependent pathways,
peroxidation by CAT, and by an unknown third pathway; conversely, primates do not appear to
exhibit such capacity and are more sensitive to metabolic acidosis following methanol poisoning
(R. J. Cook etal.. 2001).
3.2. KEY STUDIES
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Some recent toxicokinetic and metabolism studies (Burbacher. Grant, et al.. 1999; Burbacher.
Grant, et al.. 2004; Dorman et al.. 1994; Medinsky et al.. 1997; Pollack & Brouwer. 1996;
Sweeting et al.. 2010; 2011) provide key information on interspecies differences, methanol
metabolism during gestation, metabolism in the nonhuman primate, and the impact of folate
deficiency on the accumulation of formate.
[The following replaces page 3-12, line 10 to page 3-12, line 23 in March 2011 Tox Review 1
The Pollack and Brouwer (1996) study was useful for comparing effects in pregnant and NP
rodents exposed to high doses, but the implication of these results for humans exposed to
ambient levels of methanol is not clear (2004).
Sweeting et al. (2010; 2011) studied methanol and formic acid pharmacokinetics in male
C57BL/6 mice, male C3H mice, male CD-I mice, male NZW rabbits and male cynomolgous
monkeys (Macaca fasciculciris) following a 0.5 or 2 g/kg ip exposure to methanol. Blood
samples were taken over the entire methanol elimination period for rabbits (48 hours) and CD-I
mice (12 hours for 0.5 g/kg exposure; 24 hours for 2 g/kg exposure), over a 12-hour exposure
window for the C57BL/6 and C3H mice and a 6-hour post exposure window for monkeys.
Following the 2g/kg dose, methanol blood levels exhibited saturated elimination kinetics in all
three species, and peak methanol concentrations were similar (68. 87 and 79±10 mmol/L in
C57BL/6. C3H and CD-I mice, respectively; 114±7 mmol/L in rabbits and 94±14 mmol/L in
monkeys), though the peak concentrations in C57BL/6 (p<0.01) and CD-I (p<0.05) mice were
significantly lower than rabbits. Methanol clearance rates were 2.5-fold higher in CD-I mice
than in rabbits after the 2 g/kg exposure, and 2-fold higher after the 0.5 g/kg exposure. When
measured over the entire elimination period, plasma methanol AUCs in the rabbits were 175±27
after a 0.5 g/kg dose and 1893±345 mmol/L x hr after a 2 g/kg dose. Comparable plasma
methanol AUCs in CD-I mice were more than 2-fold lower. 71=1=9 after a 0.5 g/kg dose and
697=1=50 mmol/L x hr after a 2 g/kg dose. At 12-hours. the plasma methanol AUC values for
C57BL/6. C3H and CD-I mice were 465=1=14. 550=1=30 and 640=1=33 mmol/L x hr. respectively,
and rabbits had an AUC value of 969=1=77 mmol/L x hr. The elimination period plasma formic
acid AUCs in the rabbits were 3.02=1=1.3 after a 0.5 g/kg dose and 10.6=1=1.4 mmol/L x hr after a 2
g/kg dose. In comparison, plasma formic acid AUCs in CD-I mice were nearly 6-fold lower at
0.5 g/kg (71=1=9 mmol/L x hr) and more than 3-fold lower at 2 g/kg (697=1=50 mmol/L x hr). At
12-hours. the plasma formic acid AUC values for C57BL/6. C3H and CD-I mice were 2.1=1=0.3.
1.6=1=0.2 and 1.9=1=0.15 mmol/L x hr. respectively, and rabbits had a formic acid AUC value of
3.0=1=0.3 mmol/L x hr. All of the 12-hour formic acid AUCs for the mice were significantly lower
(p<0.05) than the rabbit, but none of the mouse strains differed from each other (p<0.05).
Formic acid accumulation at 6-hours post-exposure in monkeys (7.75=1=3.5 mmol/L x hr) was 5-
fold and 43-fold higher than in rabbits (1.5=1=0.2 mmol/L x hr) and CD-I mice (0.15=1=0.04
mmol/L x hr). respectively.
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Burbacher, Shen et al. (1999; 2004) examined toxicokinetics in Macaca fascicalaris
monkeys prior to and during pregnancy. The study objectives were to assess the effects of
repeated methanol exposure on disposition kinetics, determine whether repeated methanol
exposures result in formate accumulation, and examine the effects of pregnancy on methanol
disposition and metabolism. Reproductive, developmental and neurological toxicity associated
with this study were also examined and are discussed in Sections 4.3.2 and 4.4.2. In a 2-cohort
design, 48 adult females (6 animals/dose/group/cohort) were exposed to 0, 200, 600, or
1,800 ppm methanol vapors (99.9% purity) for 2.5 hours/day, 7 days/week for 4 months prior to
breeding and during the entire breeding and gestation periods. Six-hour methanol clearance
studies were conducted prior to and during pregnancy. Burbacher, Shen et al. (1999; 2004)
reported that:
4.3.3. Other Reproductive and Developmental Toxicity Studies
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Additional information relevant to the possible effects of methanol on reproductive and
developmental parameters has been provided by experimental studies that have exposed
experimental animals to methanol during pregnancy via i.p. injections (J. M. Rogers et al.. 2004;
Sweeting et al.. 2011). Relevant to the developmental impacts of the chemical, a number of
studies also have examined the effects of methanol when included in whole-embryo culture (J. E.
Andrews et al.. 1995; J. E. Andrews et al., 1993; J. E. Andrews et al.. 1998; Hansen et al.. 2005;
Harris et al.. 2003).
Sweeting et al. (2011) performed a series of experiments in NZW rabbits. C57BL/6J
mice and C3H mice to compare plasma pharmacokinetics of methanol and formic acid and
embryotoxicitv. For the pharmacokinetic portion of the study, male mice and rabbits were given
a single i.p. dose of 2 g methanol/kg body weight or its saline vehicle control. For the teratology
portion of the study, pregnant female mice and rabbits were given two i.p. doses of 2 g
methanol/kg body weight on GD 7 or 8. for a total daily dose of 4 g methanol/kg body weight, or
two i.p. doses of a saline vehicle control. Methanol exposure did not significantly impact fetal
body weights for any of the species and strains tested. No statistically significant effects were
reported on rabbit growth parameters and mortality. However, postpartum lethality was nearly
2-fold higher in the methanol exposed (11%) versus control (5%) fetuses, and stillbirths were
also increased (4% versus 0%). Though these increased incidences were not statistically
significant, they may be biologically significant given that postpartum lethality ("wasting
syndrome") and a shortened gestational period were possible adverse outcomes observed in
methanol exposed monkeys (see discussion of Burbacher. Shen et al.. 1999; 2004 in Section
4.3.2). A 4.4-fold increase in tail abnormalities per litter, including shortening and absence, was
reported in rabbit fetuses. However, due to the variability of this endpoint among litters, this
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difference was not statistically significant. Non-significant increases were reported in exposed
rabbit litters for several other effects that were not observed in controls, including two fetuses
with open posterior neuropores. one with an abdominal wall defect (prune belly), and three with
frontal nasal hyperplasia. In C3H mice, methanol in utero exposure caused a 2-fold increase in
fetal resorptions, but this increase was not statistically significant over saline treated controls
(p<0.01). In C57BL/6. methanol caused a 66% incidence of fetal ophthalmic abnormalities
(PO.OOl) compared to a non-significant 3% incidence in C3H mice. Ophthalmic anomalies
were not observed in saline-exposed controls of either strain. Methanol also caused a 17%
increase in fetal cleft palates in C57BL/6 mice (p<0.05) compared to 0% in saline controls, and
0% in C3H mice treated with either methanol or saline. No increase in cephalic NTDs. an
endpoint commonly observed in CD-I mice, was observed in C57BL/6 or C3H mice. The
different teratological results across these mouse strains could not be explained by differences in
methanol or formic acid disposition (the pharmacokinetic results of this study are described in
Section 3.2). The authors hypothesize that these differences in embryotoxicitv could be due to
strain differences in ADH activity and the amount of catalase available for ROS detoxification,
or differences in other pathways that involve ROS formation.
Pregnant female C57BL/6J mice received 2 i.p. injections of methanol on GD7 (J. M.
Rogers et al.. 2004). The injections were given 4 hours apart to provide a total dosage of 0, 3.4,
and 4.9 g/kg. Animals were sacrificed on GDI7 and the litters were examined for live, dead, and
resorbed fetuses. Rogers et al. (2004) monitored fetal weight and examined the fetuses for
external abnormalities and skeletal malformations. Methanol-related deficits in maternal and
litter parameters observed by Rogers et al. (2004) are summarized in Table 4-8.
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In contrast to the in vitro and in vivo findings of Dorman et al. (1995). Andrews et al.
(1995) demonstrated that formate can induce similar developmental lesions in whole rat and
mouse conceptuses was demonstrated by Andrews et al. (1995). who evaluated the
developmental effects of sodium formate and formic acid in rodent whole embryo cultures in
vitro. Day 9 rat (Sprague-Dawley) embryos were cultured for 24 or 48 hours and day 8 mouse
(CD-I) cultures were incubated for 24 hours. As tabulated by the authors, embryos of either
species showed trends towards increasing lethality and incidence of abnormalities with exposure
concentration. Among the anomalies observed were open anterior and posterior neuropores, plus
rotational defects, tail anomalies, enlarged pericardium, and delayed heart development.
4.6.3. Methanol-Induced Formation of Free Radicals, Lipid Peroxidation, and Protein
Modifications
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[The following replaces page 4-72, line 21 to page 4-73, line 6 in March 2011 Tox Reviewl
Oxidative stress in mother and offspring has been suggested to be part of the teratogenic
mechanism of a related alcohol, ethanol. Certain reproductive and developmental effects (e.g.,
resorptions and malformation rates) observed in Sprague-Dawley rats following ethanol
exposure were reported to be ameliorated by antioxidant (Vitamin E) treatment (Wentzel &
Eriksson. 2006; Wentzel et al.. 2006). A number of studies have examined markers of oxidative
stress associated with methanol exposure.
McCallum et al. (201 la.b) treated adult male CD-I mice. DNA repair deficient
oxosuanine glvcosvlase (Oggl) knockout mice. NZW rabbits and cvnomolsus monkeys
(Macaca fascicular is) with a single i.p. injection of 2g/kg methanol and measured 8-hydroxy-2'-
deoxyguanosine (8-oxodG). as an indicator of tissue oxidative DNA damage. 6 hours post-
injection in the lung, liver, kidney, bone marrow and spleen. They also examined these organs
for 8-oxodG in adult male CD-I mice injected daily for 15 days with 2 g/kg methanol. They
reported no evidence of methanol-dependent increases in 8-oxodG in any of the species and
organ systems tested.
Skrzydlewska et al. (2005) provided inferential evidence for the effects of methanol on
free radical formation, lipid peroxidation, and protein modifications, by studying the protective
effects of N-acetyl cysteine and the Vitamin E derivative, U83836E, in the liver of male Wistar
rats exposed to the compound via gavage. Forty-two rats/group received a single oral gavage
dose of either saline or 50% methanol. This provided a dose of approximately 6,000 mg/kg, as
calculated by the authors. Other groups of rats received the same concentration of methanol, but
were also injected intraperitoneal^ with either N-acetyl cysteine or U-83836E. N-acetyl cysteine
and U-83836E controls were also included in the study design. Animals in each group were
sacrificed after 6, 14, and 24 hours or after 2, 5, or 7 days. Livers were rapidly excised for
electron spin resonance (ESR) analysis, and 10,000 x g supernatants were used to measure GSH,
malondialdehyde, a range of protein parameters, including free amino and sulfhydryl groups,
protein carbonyls, tryptophan, tyrosine, and bityrosine, and the activity of cathepsin B.
4.8. NONCANCER MOA INFORMATION
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While it is well established that the toxic consequences of acute methanol poisoning arise
from the action of formate, there is less certainty on how the toxicological impacts of longer-
term exposure to lower levels of methanol are brought about. For example, since developmental
effects in experimental animals appear to be significant adverse effects associated with in utero
methanol exposure, it is important to determine potential MO As for how these specific effects
are brought about.
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Sweeting et al. (2011) have postulated that mouse embryo tissue may have a high
sensitivity to oxidative damage relative to other species due to a strong reliance on catalase over
ADH to metabolize embryonic methanol. The authors suggest that the low ADH activity in
mouse embryo relative to rats (Harris et al.. 2003; Section 4.3.3). combined with the preference
of catalase to metabolize methanol over hydrogen peroxide, could lead to a greater depletion of
catalase and a higher level of ROS in mouse versus rat embryos, partially explaining the higher
sensitivity of mice to the embryotoxic effects of methanol. If ROS accumulation due to this
catalase consumption makes a significant contribution to methanol teratogenicity in sensitive
mouse strains, then sensitive mouse strains may not adequately reflect risk to humans, assuming
human fetuses do not rely on catalase for methanol metabolism. However, there is reason to
believe that human infants can metabolize methanol via a mechanism other than ADH. and that
this alternative mechanism could involve catalase (Tran et al.. 2007). As discussed in Section
3.3. ADH activity in human fetuses and infants is as low as 10% and 20% of adult activity,
respectively (Pikkarainen and Raiha. 1967; Smith et al.. 1971). Yet, some human infants are still
able to efficiently eliminate methanol at high exposure levels (Tran et al.. 2007).
As described in Section 4.6.1, data from experiments carried out by Dorman et al. (1995).
formate is not the probable proximate teratogen in pregnant CD-I mice exposed to high
concentrations of methanol vapor. This conclusion is based on the fact that there appeared to be
little, if any, accumulation of formate in the blood of methanol-exposed mice, and exencephaly
did not occur until formate levels were grossly elevated. Another line of argument is based on
the observation that treatment of pregnant mice with a high oral dose of formate did not induce
neural tube closure defects at media concentrations comparable to those observed in uterine
decidual swelling after maternal exposure to methanol. Lastly, methanol- but not formate-
induced neural tube closure defects in mouse embryos in vitro at media concentrations
comparable to the levels of methanol detected in blood after a teratogenic exposure.
[The following replaces page 4-86, line 6 in March 2011 Tox Reviewl
In adult humans, metabolism of methanol occurs primarily through ADH1, whereas in rodents
5.3.8. Choice of Species/Gender
[The following replaces page 5-32, line 1 to line 5 in March 2011 Tox Reviewl
The RfC and RfD were based on decreased brain weight at 6 weeks postbirth in male rats
(the gender most sensitive to this effect) (NEDO. 1987). This decrease in brain weight also
occurs in female rats; however, if the decreased brain weight in female rats had been used, higher
RfC and RfD values would have been derived (approximately 66% higher than the male derived
values). As shown in Table 5-4, the HEC POD of 182 mg/m3 derived from the NEDO (1987) rat
study was lower than the HEC POD derived from the Rogers et al. (1993) mouse study, but
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slightly higher than the HEC POD derived from the Burbacher et al. (1999) monkey study. As
discussed in Section 5.3.1, while existing developmental and chronic studies suggest that
monkeys may be the more sensitive and relevant species, the substantial deficits and
uncertainties in the reported data preclude their use for derivation of an RfC. The Rogers et al.
(1993) mouse study was not chosen as the basis for the RfC because it results in a higher HEC
POD than the chosen rat study. Sweeting et al. (2011) have suggested that mouse embryos may
not be a suitable endpoint for assessing human risk because they postulate that mouse embryos
have a relatively high sensitivity to oxidative damage due to a relatively high reliance on catalase
over ADH to metabolize embryonic methanol. If ROS accumulation due to this catalase
consumption makes a significant contribution to methanol teratogenicity in sensitive mouse
strains, then sensitive mouse strains may not adequately reflect risk to humans, assuming human
fetuses do not rely on catalase for methanol metabolism. However, there is reason to believe that
human infants can metabolize methanol via a mechanism other than ADH. and that this
alternative mechanism could involve catalase (Tran et al.. 2007). As discussed in Section 3.3.
ADH activity in human fetuses and infants is as low as 10% and 20% of adult activity,
respectively (Pikkarainen and Raiha. 1967; Smith et al.. 1971). Yet, some human infants are still
able to efficiently eliminate methanol at high exposure levels (Tran et al.. 2007).
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References
Sweeting JN. Siu M. McCallum GP. Miller L. Wells PG. (2010) Species differences in
methanol and formic acid pharmacokinetics in mice, rabbits and primates. Toxicology and
Applied Pharmacology 247: 28-35.
Sweeting JN. Siu M. Wiley MJ. Wells PG. (2011) Species- and strain-dependent teratogenicity
of methanol in rabbits and mice. Reproductive Toxicology 31: 50-58.
McCallum GP. Siu M. Sweeting JN. Wells PG. (2011) Methanol exposure does not produce
oxidatively damaged DNA in lung, liver or kidney of adult mice, rabbits or primates.
Toxicology and Applied Pharmacology 250: 147-153.
McCallum GP. Siu M. Ondovcik SL. Sweeting JN. Wells PG. (2011) Methanol Exposure Does
Not Lead to Accumulation of Oxidative DNA Damage in Bone Marrow and Spleen of Mice.
Rabbits or Primates. Molecular Carcinogenesis 50: 163-172.
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