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PubMed1994

Formate in serum and urine after controlled methanol exposure at the threshold limit value.

Methanol will be present as a new air pollutant when methanol-powered vehicles are introduced in the United States. Little is known about the effect of low-dose methanol exposure. It is controversial whether or not formate, the main metabolite responsible for methanol's acute toxicity, is a sensitive biological marker of toxicity or exposure. We studied the effect of a 4-hr exposure at rest to 200 ppm of methanol vapors on endogenous serum formate and on urinary formic acid excretion. A randomized, double-blind study of human exposure to a constant concentration of methanol was performed in a whole-body exposure chamber. Twenty-six healthy volunteers, each serving as his or her own control, participated in sham and methanol exposures. Urine (at 0, 4, 8 hr) and serum specimens (15 time points over 8 hr) collected before, during, and after the exposure were measured for formate. We found no significant differences in serum formate concentration between exposure and control conditions either at any time point or for area under the curve. Mean concentrations at the end of the exposure were: exposed 14.28 +/- 8.90 mg/l and control 12.68 +/- 6.43 mg/l. A slight, but nonsignificant (p = 0.08), increase in urine formate excretion rate was found at 4 hr (exposed 2.17 +/- 1.69 mg/4 hr and control 1.67 +/- 1.02 mg/4 hr). Age, sex, folic acid level, and smoking were not significant covariates. At 200 ppm, methanol exposure does not contribute substantially to endogenous formate quantities. Serum and urine formate determinations are not sensitive biological markers of methanol exposure at the threshold limit value.

Absorption↗
PubMed2000

Thermophilic sulfate reduction and methanogenesis with methanol in a high rate anaerobic reactor.

Sulfate reduction outcompeted methanogenesis at 65 degrees C and pH 7.5 in methanol and sulfate-fed expanded granular sludge bed reactors operated at hydraulic retention times (HRT) of 14 and 3.5 h, both under methanol-limiting and methanol-overloading conditions. After 100 and 50 days for the reactors operated at 14 and 3.5 h, respectively, sulfide production accounted for 80% of the methanol-COD consumed by the sludge. The specific methanogenic activity on methanol of the sludge from a reactor operated at HRTs of down to 3.5 h for a period of 4 months gradually decreased from 0. 83 gCOD. gVSS(-1). day(-1) at the start to a value of less than 0.05 gCOD. gVSS(-1). day(-1), showing that the relative number of methanogens decreased and eventually became very low. By contrast, the increase of the specific sulfidogenic activity of sludge from 0. 22 gCOD. gVSS(-1). day(-1) to a final value of 1.05 gCOD. gVSS(-1). day(-1) showed that sulfate reducing bacteria were enriched. Methanol degradation by a methanogenic culture obtained from a reactor by serial dilution of the sludge was inhibited in the presence of vancomycin, indicating that methanogenesis directly from methanol was not important. H(2)/CO(2) and formate, but not acetate, were degraded to methane in the presence of vancomycin. These results indicated that methanol degradation to methane occurs via the intermediates H(2)/CO(2) and formate. The high and low specific methanogenic activity of sludge on H(2)/CO(2) and formate, respectively, indicated that the former substrate probably acts as the main electron donor for the methanogens during methanol degradation. As sulfate reduction in the sludge was also strongly supported by hydrogen, competition between sulfate reducing bacteria and methanogens in the sludge seemed to be mainly for this substrate. Sulfate elimination rates of up to 15 gSO(4)(2-)/L per day were achieved in the reactors. Biomass retention limited the sulfate elimination rate.

Acetates↗
PubMed2001

Effect of 4-methylpyrazole on endogenous plasma ethanol and methanol levels in humans.

BACKGROUND: Endogenous methanol and ethanol levels are found in human blood. It is assumed that these compounds are derived mainly from microflora in the gastrointestinal tract and that the small amounts formed are consequently eliminated, mainly in the liver, by the alcohol dehydrogenase (ADH) pathway. The objective of the present study was to investigate the effect of 4-methylpyrazole (4-MP), a specific ADH inhibitor, on endogenous plasma methanol and ethanol levels in healthy women and men. METHODS: A double-blind placebo-controlled interventional study was carried out. RESULTS: A significant elevation in plasma endogenous ethanol and methanol levels was observed after intake of 4-MP (10-15 mg/kg p.o.). For methanol levels, a linear increase from 20 +/- 14 micromol/l before intake to 39 +/- 22 micromol/l at 420 min from intake of 4-MP (levels 20 +/- 14 micromol/l and 14 +/- 9 micromol/l during the corresponding placebo time points) was found. For ethanol, concentrations increased from levels below detection limit (i.e., < 5 micromol/l, determined by headspace gas chromatography) before intake to 30 +/- 20 micromol/l at 195 min from intake of 4-MP. A small increase in ethanol levels, to 13 +/- 8 micromol/l, but not in methanol levels, was observed after the intake of lingonberry juice containing no ethanol or methanol. No sex differences in the ethanol and methanol levels before or after the intake of 4-MP were found. CONCLUSIONS: The present study provides conclusive evidence for a constant endogenous production as well as clearance of ethanol and methanol in humans. In addition, the study shows that the ethanol and methanol produced are, at least in part, eliminated by the ADH pathway.

Adult↗
PubMed2003

Acute methanol poisonings reported to the Drug and Poison Information Center in Izmir, Turkey.

The demographics, sources and outcomes of methanol poisoning have not been described in Turkey. Our study identified the profile of acute methanol exposures reported to Drug and Poison Information Center (DPIC) in Izmir, Turkey, from 1993 to 2002. Data analysis included patient demographics, sources of methanol, reason for the exposure, clinical effects and outcomes of methanol poisoning. The DPIC recorded 30,485 calls concerning poisoning; 996 (3.3%) alcohol poisonings were recorded and 113 (11.3%) of them were methanol poisonings. There were 91 (80.5%) males and 22 (19.5%) females with a mean age of 34.7+/-1.3 y (range 19-65) and 4.8+/-0.9 y (range 1-18) in adults and children, respectively. The sources of methanol were eu de cologne (72.6%), spirits (10.6%) and antifreeze (2.7%). Accidental poisoning occurred in all children between 0 and 12 y old, abuse (55.7%) and intentional poisoning (27.3%) were predominant in adults. Clinical signs in all cases were central nervous system symptoms (45.1%), metabolic acidosis (23.0%), visual symptoms (21.2%) and gastrointestinal symptoms (10.6%). Sixteen patients (14.1%) died, 63 (55.8%) had complete recovery and 1 (0.9%) had irreversible visual problems. Most patients with methanol poisoning may die or present serious morbidity without appropriate treatment in a health care facility. Methanol for producing cheap "eu de colognes" in Turkey is the principal reason for severe poisoning and deaths. Public education about colognes and legislative control of cologne production are important in preventing methanol poisoning.

Adolescent↗
PubMedDate not supplied

Methanol induced biogenic amine changes in discrete areas of rat brain: role of simultaneous ethanol administration.

Alteration in the steady state level of brain biogenic amines produced by methanol differ considerably in rats when compared to the effects produced by ethanol. When ethanol and methanol were administered simultaneously in identical concentration, the effects produced by methanol were much more pronounced in the presence of ethanol. This could be attributed to the delay in the metabolism of methanol as ethanol competes with methanol for alcohol dehydrogenase enzyme activity. Hence, it is presumed that the effects produced by methanol seem to be primarily due to the direct action of methanol itself and not due to metabolic end products of methanol. It is also inferred that if methanol per se is going to produce any permanent damage in the central nervous system due to abnormal neurotransmitter behaviour, they cannot be prevented by treatment with ethanol.

Animals↗
PubMed1994

Embryotoxicity of methanol in well-nourished and malnourished rats.

1. The objective of the present study was to investigate whether maternal protein-energy malnutrition alters methanol-induced embryotoxic effects in rats. 2. On day 0 of pregnancy, dams were assigned at random to one of the following treatment groups: well-nourished methanol (WNM), well-nourished control (WNC), malnourished methanol (MNM) and malnourished control (MNC). Malnourished animals received half of the well-nourished food intake (ca 12 g/day) throughout pregnancy. Methanol was administered by gavage (2.5 g/kg body weight) from gestation day 6 to 15. 3. Rats were weighed on days 0, 6 to 15, and 21 of pregnancy. On day 21 rats were submitted to cesarean section. The number of implantations, living and dead fetuses, resorptions and corpora lutea was recorded. All fetuses were weighed, examined for externally visible malformations, fixed, and examined for skeletal anomalies after clearing and staining with Alizarin Red S. 4. An increased proportion of fetuses with skeletal malformations, particularly cervical extra ribs, was found in the methanol-treated groups (fetuses with skeletal malformations: WNC = 5.6%, WNM = 45.4%, MNC = 3.8%, and MNM = 38.8%). Malnutrition produced fetal growth retardation, but did not cause any increase in the occurrence of gross structural malformations. The methanol-induced increase in the proportion of fetuses with extra ribs was not altered by malnutrition, but methanol potentiated the malnutrition-induced increase in the proportion of fetuses with signs of delayed ossification (WNC = 18.6%, WNM = 25.4%, MNC = 39.7%, and MNM = 78.4%). 5. These findings suggest that methanol-induced gross structural malformations are not affected by maternal malnutrition, but the delay in ossification caused by malnutrition is aggravated by treatment with methanol.

Animals↗
PubMed1996

Comparative toxicokinetics of methanol in pregnant and nonpregnant rodents.

Methanol toxicokinetics were examined in pregnant Sprague-Dawley rats and CD-1 mice to explore the possibility of gestational-associated alterations in metabolism and disposition. In vitro biotransformation of methanol in rat and mouse fetal livers also was examined to assess the capability of the near-term rodent fetus to metabolize methanol. In the in vivo studies, rats received a single dose (100 or 2,500 mg/kg) of methanol either orally (by gavage) or intravenously; mice received a single oral or intravenous 2500-mg/kg dose. The maximal rate of methanol elimination (Vmax) in vivo decreased at term in both rodent species; Vmax in near-term rats and mice was only 65-80% of that in nonpregnant animals. Gestation also affected intercompartmental transfer rate constants, although there was no obvious relationship between these changes and gestational stage. In vitro metabolism studies supported the in vivo data; adult near-term rodent livers metabolized methanol with a Vmax of approximately 85% that in livers from nonpregnant rodents (p < 0.05). Fetal rodent liver was capable of metabolizing methanol in vitro, but only at a rate < 5% of respective adult livers. Data generated in these experiments demonstrate that alterations in methanol disposition associated with gestational stage must be accounted for in the development of a toxicokinetic model for methanol in pregnant mammals.

Administration, Oral↗
PubMed2006

Effects of methanol on the thermodynamics of iron(III) [tetrakis(pentafluorophenyl)]porphyrin chloride dissociation and the creation of catalytically active species for the epoxidation of cyclooctene.

In a previous study, the authors showed that iron(III) [tetrakis(pentafluorophenyl)]porphyrin chloride [(F20TPP)FeCl] is catalytically inactive for cyclooctene epoxidation by hydrogen peroxide in acetonitrile but is catalytically active if the solvent contains methanol. It was suggested that the precursor to the active species is (F20TPP)Fe(OCH3) in methanol-containing solvents. The present study was aimed at evaluating this hypothesis. (F20TPP)Fe(OCH3) was synthesized and characterized by 1H NMR but was found to be inactive in both acetonitrile and methanol. Further investigation of the interactions of (F20TPP)FeCl with methanol in acetonitrile/methanol mixtures was then carried out using NMR. Two species, characterized by 1H NMR resonances at 82 and 65 ppm, were observed. The first resonance is attributed to the beta-pyrrole protons on molecularly dissolved (F20TPP)FeCl, whereas the second is attributed to beta-pyrrole protons of [(F20TPP)Fe]+ cations that are stabilized by coordination with a molecule of methanol, viz., [(F20TPP)Fe(CH3OH)]+. The relative concentration of [(F20TPP)Fe(CH3OH)]+ increases as the fraction of methanol in the solvent increases, suggesting that methanol facilitates the dissociation of (F20TPP)FeCl into cations and anions. A thermodynamic model of the dissociation is proposed and found to describe successfully the experimental observation over a range of solvent compositions, porphyrin concentrations, and temperatures. UV-visible spectroscopy was also used to validate the developed model. In addition, the observed rate constant for cyclooctene epoxidation was found to be proportional to the concentration of [(F20TPP)Fe(CH3OH)]+ calculated using the thermodynamic model, suggesting that this intermediate is a precursor to the species that catalyzes olefin epoxidation. The catalytic activity of [(F20TPP)Fe(CH3OH)]+ was further confirmed through experiments in which (F20TPP)Fe(OCH3) dissolved in methanol was reacted with HCl(aq). This reaction produced a product with an NMR peak at 65 ppm attributable to [(F20TPP)Fe(CH3OH)]+, and this mixture was found to have activity for cyclooctene epoxidation similar to that of (F20TPP)FeCl dissolved in methanol.

Journal Article↗
PubMed2005

Structure of the liquid-vapor interface of water-methanol mixtures as seen from Monte Carlo simulations.

Monte Carlo simulation of the vapor-liquid interface of water-methanol mixtures of different compositions, ranging from pure water to pure methanol, have been performed on the canonical (N, V, T) ensemble at 298 K. The analysis of the systems simulated has revealed that the interface is characterized by a double layer structure: methanol is strongly adsorbed at the vapor side of the interface, whereas this adsorption layer is followed at its liquid side by a depletion layer of methanol of lower concentration than in the bulk liquid phase of the system. The dominant feature of the interface has been found to be the adsorption layer in systems of methanol mole fractions below 0.2, and the depletion layer in systems of methanol mole fractions between 0.25 and 0.5. The orientation of the molecules located at the depletion layer is found to be already uncorrelated with the interface, whereas the methanol molecules of the adsorption layer prefer to align perpendicular to the interface, pointing straight toward the vapor phase by their methyl group. Although both the preference of the molecular plane for a perpendicular alignment with the interface and the preference of the methyl group for pointing straight to the vapor phase are found to be rather weak, the preference of the methyl group for pointing as straight toward the vapor phase as possible within the constraint imposed by the orientation of the molecular plane is found to be fairly strong. One of the two preferred orientations of the interfacial water molecules present in the neat system is found to disappear in the presence of methanol, because methanol molecules aligned in their preferred orientation can replace these water molecules in the hydrogen-bonding pattern of the interface.

Journal Article↗
PubMed2006

Ab initio molecular dynamics simulation of the structure and proton transport dynamics of methanol-water solutions.

Ab initio molecular dynamics simulations are employed to study the structural and proton transport properties of methanol-water mixtures. Structural characteristics analyzed at two different methanol mole fractions (X(M) = 0.25 and X(M) = 0.5) reveal enhanced structuring of water as the methanol mole fraction increases in agreement with recent neutron diffraction experiments. The simulations reveal the existence of separate hydrogen-bonded water and methanol networks, also in agreement with the neutron diffraction data. The addition of a single proton to the X(M) = 0.5 mixture leads to an anomalous structural or Grotthuss-type diffusion mechanism of the charge defect in which water-to-water, methanol-to-water, and water-to-methanol proton transfer reactions play the dominant role with methanol-to-methanol transfers being much less significant. Unlike in bulk water, where coordination number fluctuations drive the proton transport process, suppression of the coordination number of waters in the first solvation shell of the defect diminish the importance of coordination number fluctuations as a driving force in the structural diffusion process. The charge defect is found to reside preferentially at the interface between water and methanol networks. The length of the ab initio molecular dynamics run (approximately 120 ps), allowed the diffusion constant of the charge defect to be computed, yielding a value of D = 4.2 x 10(-5) cm2/s when deuterium masses are assigned to all protons in the system. The relation of this value to excess proton diffusion in bulk water is discussed. Finally, a kinetic theory is introduced to identify the relevant time scales in the proton transfer/transport process.

Journal Article↗
PubMed2006

Characterization and methanol electrooxidation studies of Pt(111)/Os surfaces prepared by spontaneous deposition.

Catalytic activity of the Pt(111)/Os surface toward methanol electrooxidation was optimized by exploring a wide range of Os coverage. Various methods of surface analyses were used, including electroanalytical, STM, and XPS methods. The Pt(111) surface was decorated with nanosized Os islands by spontaneous deposition, and the Os coverage was controlled by changing the exposure time to the Os-containing electrolyte. The structure of Os deposits on Pt(111) was characterized and quantified by in situ STM and stripping voltammetry. We found that the optimal Os surface coverage of Pt(111) for methanol electrooxidation was 0.7 +/- 0.1 ML, close to 1.0 +/- 0.1 Os packing density. Apparently, the high osmium coverage Pt(111)/Os surface provides more of the necessary oxygen-containing species (e.g., Os-OH) for effective methanol electrooxidation than the Pt(111)/Os surfaces with lower Os coverage (vs e.g., Ru-OH). Supporting evidence for this conjecture comes from the CO electrooxidation data, which show that the onset potential for CO stripping is lowered from 0.53 to 0.45 V when the Os coverage is increased from 0.2 to 0.7 ML. However, the activity of Pt(111)/Os for methanol electrooxidation decreases when the Os coverage is higher than 0.7 +/- 0.1 ML, indicating that Pt sites uncovered by Os are necessary for sustaining significant methanol oxidation rates. Furthermore, osmium is inactive for methanol electrooxidation when the platinum substrate is absent: Os deposits on Au(111), a bulk Os ingot, and thick films of electrodeposited Os on Pt(111), all compare poorly to Pt(111)/Os. We conclude that a bifunctional mechanism applies to the methanol electrooxidation similarly to Pt(111)/Ru, although with fewer available Pt sites. Finally, the potential window for methanol electrooxidation on Pt(111)/Os was observed to shift positively versus Pt(111)/Ru. Because of the difference in the Os and Ru oxophilicity under electrochemical conditions, the Os deposit provides fewer oxygen-containing species, at least below 0.5 V vs RHE. Both higher coverage of Os than Ru and the higher potentials are required to provide a sufficient number of active oxygen-containing species for the effective removal of the site-blocking CO from the catalyst surface when the methanol electrooxidation process occurs.

Journal Article↗
PubMed1989

Organization of Genes Required for the Oxidation of Methanol to Formaldehyde in Three Type II Methylotrophs.

Restriction maps of genes required for the synthesis of active methanol dehydrogenase in Methylobacterium organophilum XX and Methylobacterium sp. strain AM1 have been completed and compared. In these two species of pink-pigmented, type II methylotrophs, 15 genes were identified that were required for the expression of methanol dehydrogenase activity. None of these genes were required for the synthesis of the prosthetic group of methanol dehydrogenase, pyrroloquinoline quinone. The structural gene required for the synthesis of cytochrome c(L), an electron acceptor uniquely required for methanol dehydrogenase, and the genes encoding small basic peptides that copurified with methanol dehydrogenases were closely linked to the methanol dehydrogenase structural genes. A cloned 22-kilobase DNA insert from Methylsporovibrio methanica 81Z, an obligate type II methanotroph, complemented mutants that contained lesions in four genes closely linked to the methanol dehydrogenase structural genes. The methanol dehydrogenase and cytochrome c(L) structural genes were found to be transcribed independently in M. organophilum XX. Only two of the genes required for methanol dehydrogenase synthesis in this bacterium were found to be cotranscribed.

Journal Article↗
PubMed1986

Phenotypic characterization of 10 methanol oxidation mutant classes in Methylobacterium sp. strain AM1.

Twenty-five methanol oxidation mutants of the facultative methylotroph Methylobacterium sp. strain AM1 have been characterized by complementation analysis and assigned to 10 complementation groups, Mox A1, A2, A3, and B through H (D. N. Nunn and M. E. Lidstrom, J. Bacteriol. 166:582-591, 1986). In this study we have characterized each of the mutants belonging to the 10 Mox complementation groups for the following criteria: phenazine methosulfate-dichlorophenolindophenol dye-linked methanol dehydrogenase activity; methanol-dependent whole-cell oxygen consumption; the presence or absence of methanol dehydrogenase protein by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting; the absorption spectra of purified mutant methanol dehydrogenase proteins; and the presence or absence of the soluble cytochrome c proteins of Methylobacterium sp. strain AM1, as determined by reduced-oxidized difference spectra and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. With this information, we have proposed functions for each of the genes deficient in the mutants of the 10 Mox complementation groups. These proposed gene functions include two linked genes that encode the methanol dehydrogenase structural protein and the soluble cytochrome cL, a gene encoding a secretion function essential for the synthesis and export of methanol dehydrogenase and cytochrome cL, three gene functions responsible for the proper association of the pyrrolo-quinoline quinone prosthetic group with the methanol dehydrogenase apoprotein, and four positive regulatory gene functions controlling the expression of the ability to oxidize methanol.

Alcohol Oxidoreductases↗
PubMed2004

Methanol exposure during gastrulation causes holoprosencephaly, facial dysgenesis, and cervical vertebral malformations in C57BL/6J mice.

BACKGROUND: Exposure of pregnant outbred CD-1 mice to methanol during the period of gastrulation results in exencephaly, cleft palate, and cervical vertebra malformations [Rogers and Mole, Teratology 55: 364, 1997], while inbred C57BL/6J mice are sensitive to the teratogenicity of ethanol. C57BL/6J fetuses exhibit the holoprosencephaly spectrum of malformations after maternal exposure to ethanol during gastrulation, but the sensitivity of C57BL/6J mice to methanol-induced teratogenesis has not been previously described. METHODS: Pregnant C57BL/6J mice were administered two i.p. injections totaling 3.4 or 4.9 g/kg methanol or distilled water four hrs apart on gestation day 'GD' 7. On GD 17, litters were examined for numbers of live, dead and resorbed conceptuses, fetuses were weighed as a litter and examined externally, and all fetuses were double stained for skeletal analysis. RESULTS: No maternal intoxication was apparent, but the high dosage level caused a transient deficit in maternal weight gain. The number of live fetuses per litter was reduced at both dosages of methanol, and fetal weight was lower in the high dosage group. Craniofacial defects were observed in 55.8% of fetuses in the low dosage group and 91.0% of fetuses in the high dosage group, including micro/anophthalmia, holoprosencephaly, facial clefts and gross facial angenesis. Skeletal malformations, particularly of the cervical vertebrae, were observed at both dosages of methanol, and were similar to those previously reported in the CD-1 mouse following methanol exposure. CONCLUSIONS: The types of craniofacial malformations induced in the C57BL/6J mouse by methanol indicate that methanol and ethanol have common targets and may have common modes of action.

Abnormalities, Drug-Induced↗
PubMed1980

[Determination of intramuscular fat in beef by means of extraction with chloroform-methanol].

In a comparison on samples of muscular substance from 53 fattening bulls the extraction of intramuscular fat with a chloroform-methanol mixture yielded results about 1.23% higher than those obtained with the extraction with diethyl ether. This difference results from the extraction of additional water-soluble nitrogenous compounds by the chloroform-methanol mixture. These compounds were isolated by adding water to the chloroform-methanol extract; their analysis by means of chemical and spectroscopic methods revealed, among other compounds, creatinine and threonine. The fat values obtained for the ether extract were closely correlated with those found for the chloroform-methanol extract (r = 0.925). In a variant where water was added to the chloroform-methanol extract, the correlation was less close (r = 0.925). In a variant where water was added to the chloroform-methanol extract, the correlation was less close (r = 0.660). The chloroform-methanol extraction may be used instead of the ether extraction. A regression calculated from the present data permits, if required, to convert the values thus obtained into the values yielded by the ether extraction method. Apart from its high precision, the chloroform-methanol extraction has the special advantage that it requires relatively simple safety measures and that its energy demand is low.

Animals↗
PubMed1995

In vitro assessment of the effect of methanol and the metabolite, formic acid, on embryonic development of the rat.

Inhalation studies in rats have indicated that methanol is embryotoxic at levels that are only mildly maternally toxic. In the present study, the embryotoxicity of methanol and its metabolite, formic acid, was evaluated using rat embryo culture. The results showed that both methanol and formic acid have a concentration-dependent embryotoxic effect on the developing rat embryo in vitro. The no-effect concentration of methanol was 211.7 mumol/ml culture medium, while embryotoxicity was observed at 286.5 mumol/ml. The no-effect concentration of formic acid was 3.74 mumol/ml, while a concentration of 18.66 mumol/ml was associated with severe embryotoxicity. When embryos were grown in sera containing 18.66 mumol sodium formate/ml or in sera adjusted with hydrochloric acid to pH values similar to those achieved with formic acid, the results indicated that both low pH and formate contributed to the observed embryotoxicity of formic acid. When the level of methanol found to be embryotoxic in the present study is compared to blood levels in the human following controlled industrial exposure there appears to be a large margin of safety. However, plasma methanol levels are only one aspect of methanol toxicity in the human. Of greater significance is the formate level and the associated acidosis. However, it appears that embryotoxicity due to low pH or high formate levels would only occur after very severe methanol intoxication. Based on these in vitro studies, current industrial safety limits would appear to provide protection for the developing embryo.

Animals↗
PubMed1995

Increased endobiotic fatty acid methyl esters following exposure to methanol.

Human exposure to methanol is likely to increase in the future due to its proposed use as an alternate automobile fuel. Since alcohols are known to esterify the fatty acids in the body and some of those esterified esters are toxic, we studied the formation of fatty acid esters of methanol in Long-Evans male rats given a single oral dose of 3.5 g/kg body weight of methanol in saline. Animals given an equal volume of saline served as control. Three rats were euthanized at 1, 3, 6, 12 and 24 hr following the treatment. Fatty acid methyl esters, extracted from whole blood, liver, pancreas, and brown fat were separated by thin-layer chromatography and quantitated by gas chromatography (GC). Their identity was then confirmed by GC-mass spectrometry. Average levels as high as 596, 5293, 2239, 1106, 9665, 7728, 562, and 2792 micrograms/g (wet weight basis) of 14:0, 16:0, 16:1, 18:0, 18:1, 18:2, 18:3, and 20:4 fatty acid methyl esters, respectively, were found in the pancreas of methanol-treated rats. The average concentration of total fatty acid methyl esters was computed to be 4513, 29594, 22871, 18956, 17014, and 9702 micrograms/g in the pancreas compared to 1.9, 25.4, 36.8, 18.5, 18.9, and 14.2 micrograms/g in the liver at 0, 1, 3, 6, 12, and 24 hr, respectively, following methanol exposure. On dry lipid weight basis, the levels were significantly higher again in pancreas followed by brown fat and liver. In whole blood, only low levels of 16:0, 18:0, and 20:4 fatty acid methyl esters could be detected at all time points. The highest concentration of total fatty acid methyl esters in the pancreas, liver, and brown fat was detected at 1, 3, and 24 hr, respectively. Most of the fatty acid methyl esters found in the liver and pancreas decreased after 6 hr of methanol exposure. The fatty acid methyl esters of higher concentrations were 16:0 in the whole blood, 18:0, 18:1, 18:2, and 20:4 in liver, 18:1, and 18:2 in pancreas and 16:0, 18:1, and 18:2 in brown fat. These fatty acid methyl esters were also detected in the tissues of control rats indicating their endogenous formation. Significant increase in methylation of the fatty acids during methanol exposure, as found in this study, may serve as a defense mechanism for preventing available methanol from oxidative metabolism to render toxicity. However, the biological significance of these fatty acid methyl esters is yet to be understood.

Adipose Tissue, Brown↗
PubMed1996

Formate-induced alterations in retinal function in methanol-intoxicated rats.

Formic acid is the toxic metabolite in methanol poisoning. Permanent visual damage in methanol-intoxicated humans and non-human primates has been associated with prolonged exposures (> 24 hr) to blood formate concentrations in excess of 7 mM; however, little information is available on the toxicity associated with chronic low-level or repeated exposure to methanol. The present studies compared the effects on retinal function and structure of rapidly increasing formate concentrations typical of acute methanol intoxication with low-level plateau formate concentrations more likely to be generated by subacute or chronic methanol exposure. Rats that accumulated formate concentrations of 8-15 mM developed metabolic acidosis, retinal dysfunction, and retinal histopathologic changes. Retinal dysfunction was measured as reductions in the a- and b-waves of the electroretinogram that occurred coincident with blood formate accumulation. Histopathologic studies revealed vacuolation in the retinal pigment epithelium and photoreceptor inner segments. Rats exposed to formate concentrations ranging from 4 to 6 mM for 48 hr showed evidence of retinal dysfunction in the absence of metabolic acidosis and retinal histopathology. These data indicate that formic acid generated from methanol oxidation acts as a direct retinal toxin. Formate-induced retinal dysfunction in methanol-intoxicated rats can be produced by steadily increasing concentrations of formate and importantly can also be produced by prolonged exposure to lower concentrations of formate. Our findings substantiate evidence based on clinical case reports and a small number of epidemiological studies and support the hypothesis that the visual system toxicity produced by acute, subacute, or chronic methanol poisoning share a common mechanism.

Animals↗