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PubMed2006

Effect of methanol-induced oxidative stress on the neuroimmune system of experimental rats.

It is well known that the nervous system has increased susceptibility to methanol intoxication. The present study reveals the effect of methanol intoxication on antioxidant status, lipid peroxidation and DNA integrity in hypothalamic-pituitary-adrenal (HPA) axis organs and spleen. Non-specific and specific immune functions were analyzed. In addition, open field behavior, plasma corticosterone level and blood methanol level were estimated. Male Wistar albino rats were intoxicated with methanol (2.37 g/kg b.wt., i.p.) for 1 day, 15 and 30 days. Administration of methanol showed significant increase in enzymatic (superoxide dismutase, catalase, glutathione peroxidase), non-enzymatic (reduced glutathione and Vitamin C) antioxidants and lipid peroxidation (LPO) in hypothalamus and adrenal gland of day 1 group. However, decrease in enzymatic and non-enzymatic antioxidants with concomitant increase in LPO level were observed in 15 and 30 days groups. Plasma corticosterone level was significantly increased in day 1 and 15 days groups whereas, 30 days methanol intoxication group showed considerable decrease in corticosterone level compared with control animals. Cell-mediated immune response of footpad thickness was significantly decreased with an increased leukocyte migration inhibition. Humoral immune response of antibody titers was elevated in methanol-intoxicated groups. Neutrophil functions, adherence and phagocytic index (PI) were found to be significantly decreases. Furthermore, significant increase in the avidity index and nitro blue tetrozolium reduction was observed in the methanol exposed animals. Day 1 methanol exposed group showed increased PI compared to the control ones. Methanol exposure for 30 days showed an increased DNA fragmentation in the hypothalamus, adrenal glands, and spleen. In conclusion, exposure to methanol-induced oxidative stress disturbs the HPA-axis function altering the level of corticosterone, which lead to varied non-specific and specific immune response in experimental rats.

Animals↗
PubMed2005

Therapeutic response to single intravenous bolus administration of formate dehydrogenase in methanol-intoxicated rats.

Methanol remains to be a major public and environmental health hazard. Formic acid is the toxic metabolite responsible for the metabolic acidosis observed in methanol poisoning in humans, in non-human primates and in folate-depleted rodents. Cytochrome oxidase inhibition by formate leads to lactic acid accumulation, which contributes significantly to metabolic acidosis. Toxic effects in human beings are characterized by formic acidemia, metabolic acidosis, ocular toxicity, nervous system depression, blindness, coma and death. Elimination of formate is one of the principles of management in methanol poisoning. Hemodialysis facility is not readily available in all the places, in developing countries like India. Formate dehydrogenase (EC 1.2.1.2) acts directly over formate and converts formate into CO(2) in the presence of NAD. Effect of single intravenous bolus infusion of formate dehydrogenase, obtained from Candida boidinii; in methanol-intoxicated folate deficient rat model was evaluated. Folate depletion induced by methotrexate (MTX) treatment. Carbicarb (Carb) (equimolar solution of sodium carbonate and sodium bicarbonate) was used to treat metabolic acidosis. Experimental design consists of seven groups, namely Saline control, methanol control, MTX control, Enzyme control, MTX-methanol control, MTX-methanol-Carb and MTX-methanol-Carb-Enz group. Male wistar rats treated with MTX (0.3mg/kg) for a week, were injected (i.p.) with methanol (4 gm/kg), 12h latter, Carbicarb solution was infused, following this enzyme was infused (i.v.) in bolus. Blood samples were collected every 15 min for an hour from the cannulated left jugular vein and blood methanol, formate were estimated, respectively, with HPLC and fluorimetric assay. Blood pH, blood gases pO(2), pCO(2) and bicarbonate were monitored with blood gas analyzer in order to evaluate acid base status of the animal. Results obtained show that there is significant elimination of formate within 15 min. It may be concluded that single bolus infusion of formate dehydrogenase facilitates fast removal of formate, a highly toxic metabolite in methanol poisoning.

Acidosis↗
PubMed2006

Supercritical methanol for polyethylene terephthalate depolymerization: observation using simulator.

To apply PET depolymerization in supercritical methanol to commercial recycling, the benefits of supercritical methanol usage in PET depolymerization was investigated from the viewpoint of the reaction rate and energy demands. PET was depolymerized in a batch reactor at 573 K in supercritical methanol under 14.7 MPa and in vapor methanol under 0.98 MPa in our previous work. The main products of both reactions were the PET monomers of dimethyl terephthalate (DMT) and ethylene glycol (EG). The rate of PET depolymerization in supercritical methanol was faster than that of PET depolymerization in vapor methanol. This indicates supercritical fluid is beneficial in reducing reaction time without the use of a catalyst. We depicted the simple process flow of PET depolymerization in supercritical methanol and in vapor methanol, and by simulation evaluated the total heat demand of each process. In this simulation, bis-hydroxyethyl terephthalate (BHET) was used as a model component of PET. The total heat demand of PET depolymerization in supercritical methanol was 2.35 x 10(6)kJ/kmol Produced-DMT. That of PET depolymerization in vapor methanol was 2.84 x 10(6)kJ/kmol Produced-DMT. The smaller total heat demand of PET depolymerization in supercritical methanol clearly reveals the advantage of using supercritical fluid in terms of energy savings.

Conservation of Natural Resources↗
PubMed2003

Kinetic isotope effects of proton transfer in aqueous and methanol containing solutions, and in gramicidin A channels.

The electrochemical conductivities of HCL and DCI were measured in: H(2)O and D(2)O; in methanol and fully deuterated methanol; and in water-methanol solutions. The single channel conductances to H(+) (g(H)) and D(+) (g(D)) in various gramicidin A (gA) ion channels incorporated in glycerylmonooleate planar bilayers were also measured. Kinetic isotope effects (KIE) were estimated from the ratio of conductivity measurements. In 1 and 5 M HCl aqueous solutions and in 1 M HCl+3.7 M methanol, the KIE ( approximately 1.35) is not different from values previously determined in dilute acid solutions. This suggests that the mobility of protons in those solutions is largely determined by proton transfer. In 10 M HCl, however, where the mobility of protons is likely to be determined by hydrodynamic diffusion, the measured KIE is considerably larger (1.47). Possible causes for this effect are discussed. The KIE of proton conductivities in 5 and 50 mM HCl in methanol and d-methanol is approximately 1.15. This is considerably smaller than the ratio between conductivities of 5 mM KCl in methanol and d-methanol (1.24). The KIE values (1.22-1.37) for g(H) in gA channels in 1 M HCl are significantly larger than for other monovalent cations and consistent with H(+) transfer. Methanol reduces g(H) in gA channels. The KIE of this effect is not different from the one measured in the absence of methanol. Possible mechanisms for the methanol-induced block of H(+) conductivities in solution and gA channels are discussed.

Deuterium↗
PubMedDate not supplied

Methanol-induced neurotoxicity in pups exposed during lactation through mother: role of folic acid.

Role of folic acid on methanol-induced neurotoxicity was studied in pups at Postnatal Day (PND) 45 exposed to methanol (1%, 2% and 4%, v/v) during lactation through mothers maintained on folic acid-deficient (FD) and folic acid-sufficient (FS) diet. A gradual loss in the body weight gain was observed in the pups exposed to 2% and 4% methanol in the FD group, while FS group exhibited this alteration only at 4% exposure. The assessment of spontaneous locomotor activity (SLA) showing a significant increase in the distance travelled was observed in the 2% and 4% methanol-exposed groups in both the FS and FD animals when compared with their respective controls, but the effect was more marked in the FD group. A significant decrease in the conditioned avoidance response (CAR) was observed in pups exposed to 2% and 4% methanol in the FD group at PND 45. The results also suggest that disturbances in dopaminergic and cholinergic receptors were more pronounced in the FD group as compared to the FS group. A significant decrease in striatal dopamine levels was also observed in the FD group at 2% and 4% methanol exposure, while in the FS group, a significant decrease was exhibited only at 4% methanol exposure. An aberrant increase in the expression of Growth-Associated Protein (GAP-43), a neuron-specific growth-associated protein was observed in pups in the FD group exposed to 2% and 4% methanol, while an increase in the expression of GAP-43 in the FS group was found only at 4% methanol exposure in the hippocampal region as compared to their respective controls. Results suggests that methanol exposure during growth spurt period adversely affects the developing brain, the effect being more pronounced in FD rats as compared to FS rats, suggesting a possible role of folic acid in methanol-induced neurotoxicity.

Animals↗
PubMed1998

Pectin methylesterase regulates methanol and ethanol accumulation in ripening tomato (Lycopersicon esculentum) fruit.

We provide genetic evidence that the production of methanol in tomato fruit is regulated by pectin methylesterase (PME, EC 3.1.1.11), an enzyme that catalyzes demethoxylation of pectins. The role of PME in methanol production in tomato fruit was examined by relating the tissue methanol content to the PME enzymatic activity in wild-type Rutgers and isogenic PME antisense fruits with lowered PME activity. In the wild-type, fruit development and ripening were accompanied by an increase in the abundance of PME protein and activity and a corresponding ripening-related increase in methanol content. In the PME antisense pericarp, the level of methanol was greatly reduced in unripe fruit, and diminished methanol content persisted throughout the ripening process. The close correlation between PME activity and levels of methanol in fruit tissues from wild-type and a PME antisense mutant indicates that PME is the primary biosynthetic pathway for methanol production in tomato fruit. Interestingly, ethanol levels that were low and unchanged during ripening of wild-type tomatoes increased progressively with the ripening of PME antisense fruit. In vitro studies indicate that methanol is a competitive inhibitor of the tomato alcohol dehydrogenase (ADH, EC 1.1.1.1) activity suggesting that ADH-catalyzed production of ethanol may be arrested by methanol accumulation in the wild-type but not in the PME mutant where methanol levels remain low.

Carboxylic Ester Hydrolases↗
PubMed2002

Methanol poisoning exposures in the United States: 1993-1998.

OBJECTIVES: We investigated U.S. methanol-poisoning exposures since little recent information is available about the frequency, sources of methanol, or outcomes of individuals who consume methanol. METHODS: We reviewed human methanol exposures reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System 1993-1998. RESULTS: The mean number of cases per year was 2254. Each year 167 cases had an outcome of moderate effect, major effect, or death. One death occurred in every 183 exposures to methanol. Symptomatic cases increased abruptly from 1.8 to 2.5% for infants and children, from 14.1 to 12.3% for adolescents and adults, while the intentional exposures increased from < 1 to 21% for adolescents, and 11% for adults. Cases occurred in every decade of life but toddlers had the highest number of exposures. In 68 methanol fatalities, confusion developedfollowed by coma, hypotension, respiratory depression, and cerebral edema. Blood methanol levels were above 100mg/dL (70%), metabolic acidoses (62%), and anion gaps > 25 (100%). Methanol products were recorded, showing windshield wiper fluids to be 60.8% of exposures. Other automotive sources were 23.7%. Commercial nonautomotive products were 12.2% and pure methanol products were 2.3%. Unintentional exposures were reported in 90.3% of all cases, while 8.3% were due to intentional exposures, and 1.4% wasfor unknown or mixed reasons. Intentional exposures resulted from suspected suicides (51.2%) and from abuse and misuse (38.8%). CONCLUSIONS: Methanol poisonings continue to occur in the United States with toddlers at the highest risk for exposure, but adolescents and adults at the highest risk for life-threatening intoxications. Over half of product-identified cases were due to consumption of windshield wiperfluid. Efforts should be undertaken to minimize methanol exposures.

Adolescent↗
PubMed2000

Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model.

A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [14C]-methanol was estimated using unreported exhaled breath time course measurements of [14C]-methanol from the D.C. Dorman et al. (1994, Toxicol Appl Pharmacol. 128, 229-238) lung-only exposure study. The cumulative amount of [14C]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [14C]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [14C]-methanol. There was no apparent trend between the percent of inhaled [14C]-methanol absorbed systemically and the [14C]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [14C]-methanol blood concentrations were variable across [14C]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [14C]-methanol. Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.

Administration, Inhalation↗
PubMed2006

Mxr1p, a key regulator of the methanol utilization pathway and peroxisomal genes in Pichia pastoris.

Growth of the yeast Pichia pastoris on methanol induces the expression of genes whose products are required for its metabolism. Three of the methanol pathway enzymes are located in an organelle called the peroxisome. As a result, both methanol pathway enzymes and proteins involved in peroxisome biogenesis (PEX proteins) are induced in response to this substrate. The most highly regulated of these genes is AOX1, which encodes alcohol oxidase, the first enzyme of the methanol pathway, and a peroxisomal enzyme. To elucidate the molecular mechanisms responsible for methanol regulation, we identify genes required for the expression of AOX1. Mutations in one gene, named MXR1 (methanol expression regulator 1), result in strains that are unable to (i) grow on the peroxisomal substrates methanol and oleic acid, (ii) induce the transcription of AOX1 and other methanol pathway and PEX genes, and (iii) form normal-appearing peroxisomes in response to methanol. MXR1 encodes a large protein with a zinc finger DNA-binding domain near its N terminus that has similarity to Saccharomyces cerevisiae Adr1p. In addition, Mxr1p is localized to the nucleus in cells grown on methanol or other gluconeogenic substrates. Finally, Mxr1p specifically binds to sequences upstream of AOX1. We conclude that Mxr1p is a transcription factor that is necessary for the activation of many genes in response to methanol. We propose that MXR1 is the P. pastoris homologue of S. cerevisiae ADR1 but that it has gained new functions and lost others through evolution as a result of changes in the spectrum of genes that it controls.

Alcohol Oxidoreductases↗
PubMed2001

Defining a tolerable concentration of methanol in alcoholic drinks.

Methanol, a potent toxicant in humans, occurs naturally at a low level in most alcoholic beverages without causing harm. However, illicit drinks made from "industrial methylated spirits" [5% (v/v) methanol:95% (v/v) ethanol] can cause severe and even fatal illness. Since documentation of a no-adverse-effect level for methanol is nonexistent in the literature a key question, from the public health perspective, is what is the maximum concentration of methanol in an alcoholic drink that an adult human could consume without risking toxicity due to its methanol content? Published information about methanol-intoxicated patients is reviewed and combined with findings in studies in volunteers given small doses of methanol, as well as occupational exposure limits (OELs), to indicate a tolerable ("safe") daily dose of methanol in an adult as 2 g and a toxic dose as 8 g. The simultaneous ingestion of ethanol has no appreciable effect on the proposed "safe" and "toxic" doses when considering exposure over several hours. Thus, assuming that an adult consumes 4 x 25-ml standard measures of a drink containing 40% alcohol by volume over a period of 2 h, the maximum tolerable concentration (MTC) of methanol in such a drink would be 2% (v/v) by volume. However, this value only allows a safety factor of 4 to cover variation in the volume consumed and for the effects of malnutrition (i.e., folate deficiency), ill health and other personal factors (i.e., ethnicity). In contrast, the current EU general limit for naturally occurring methanol of 10 g methanol/l ethanol [which equates to 0.4% (v/v) methanol at 40% alcohol] provides a greater margin of safety.

Alcoholic Beverages↗
PubMedDate not supplied

Brain biogenic amine levels after methanol administration: possible mechanism of action on central monoaminergic neurons in discrete areas of brain in Wistar rat.

Alterations in the steady state level of rat brain biogenic amines - dopamine, nor-epinephrine, epinephrine, serotonin and 5-hydroxy indole acetic acid, in response to intraperitoneal administration of methanol (3g/kg b.w.) were studied in discrete areas of the rat brain. The monoamine changes induced by methanol were quite different from those induced by ethanol consumption. They were also region-specific; hypothalamus being more vulnerable for methanol-induced monoamine changes. The effects produced by methanol were correlated with the blood and brain level of methanol at the given time, suggesting that the effects were dependent upon the local concentration of methanol in different brain regions. Acidosis induced by ammonium chloride and sodium formate administration did not alter the monoamine levels and therefore, the effects of methanol were not possibly due to acidosis. Blocking or delaying the metabolism of methanol either by 4-Methyl Pyrazole and 3-Amino 1,2,4-Triazole or by simultaneous administration of ethanol resulted in the potentiation of methanol effect. Therefore, it was concluded that methanol induced changes in brain biogenic amines were due to methanol per se and not due to metabolic end products viz. formaldehyde or formic acid.

Acidosis↗
PubMed1999

Methanol modification of the electron paramagnetic resonance signals from the S(0) and S(2) states of the water-oxidizing complex of photosystem II

The Mn-derived electron paramagnetic resonance (EPR) multiline signal from the S(0) state of the water-oxidizing complex is observable only in the presence methanol. In the present study, we have characterized the effect of methanol on the EPR signals from the S(0) and S(2) states as well as on the EPR Signal II(slow) originating from the Tyrosine(D)(ox) radical. The amplitudes of the S(0) and S(2) multiline signals increase with the methanol concentration in a similar way, whereas the S(2) g=4.1 excited state signal amplitude shows a concomitant decrease. The methanol concentration at which half of the spectral change has occurred is approximately 0.2% and the effect is saturating around 5%. Methanol has an effect on the microwave power saturation of the S(2) multiline signal, as well. The microwave power at half saturation (P(1/2)) is 85 mW in the presence of methanol, whereas the signal relaxes much slower (P(1/2) approximately 27 mW) without. The relaxation of Signal II(slow) in the presence of methanol has also been investigated. The P(1/2) value of Signal II(slow) oscillates with the S cycle in a similar way as without methanol, but the P(1/2) values are consistently lower in the methanol-containing samples. From the results, we conclude that methanol modifies the magnetic properties of the S(0) and S(2) states in a similar way. The possible site and nature of methanol binding is discussed.

Journal Article↗
PubMed1996

Influence of maternal folate status on the developmental toxicity of methanol in the CD-1 mouse.

Methanol, which is detoxified via a folic acid-dependent pathway, has been shown to be teratogenic in mice. Given recent observations that the level of dietary folic acid intake may be inversely related to the occurrence of select birth defects in humans, we tested the hypothesis that dietary folic acid intake would influence the developmental toxicity of methanol. Virgin female mice were fed one of three diets containing 400 (low), 600 (marginal), or 1,200 (adequate) nmol folic acid/kg diet for 5 weeks prior to and following mating. On gestation days (GD) 6-15, dams were administered by gavage either vehicle (distilled, deionized water) or methanol at 2.0 or 2.5 g/kg body weight, twice daily. On GD 18, mice were weighed and killed and the liver, kidneys, and gravid uteri removed and weighed. Implantation sites, live and dead fetuses, and resorptions were counted; fetuses were weighed individually and examined for cleft palate and exencephaly. One third of the fetuses in each litter were examined for skeletal morphology. Maternal liver folate concentrations were approximately 40-50% lower in the low dietary folic acid groups than in the marginal and adequate groups; methanol did not affect maternal liver folate concentration at term. Maternal net gestational weight gain was lowest at the lowest dietary folate level but was not affected by methanol. Gravid uterus weights were lowest in the low dietary folic acid groups exposed to the high methanol dose and the number of live fetuses per litter was lowest in the low folic acid groups. Fetal body weights were lowest in the low folic acid groups and significantly lower in the methanol groups relative to vehicle-treated animals. Fetal crown-rump lengths were shorter in the methanol-treated groups; this parameter was not affected by folic acid treatment. Both methanol and low dietary folic acid increased the incidence of cleft palate, with the highest number of affected litters in the low dietary folic acid group. These results support the concept that maternal folate status can modulate the developmental toxicity of methanol.

Abnormalities, Drug-Induced↗
PubMed2004

Methanol exposure interferes with morphological cell movements in the Drosophila embryo and causes increased apoptosis in the CNS.

Despite the significant contributions of tissue culture and bacterial models to toxicology, whole animal models for developmental neurotoxins are limited in availability and ease of experimentation. Because Drosophila is a well understood model for embryonic development that is highly accessible, we asked whether it could be used to study methanol developmental neurotoxicity. In the presence of 4% methanol, approximately 35% of embryos die and methanol exposure leads to severe CNS defects in about half those embryos, where the longitudinal connectives are dorsally displaced and commissure formation is severely reduced. In addition, a range of morphological defects in other germ layers is seen, and cell movement is adversely affected by methanol exposure. Although we did not find any evidence to suggest that methanol exposure affects the capacity of neuroblasts to divide or induces inappropriate apoptosis in these cells, in the CNS of germ band retracted embryos, the number of apoptotic nuclei is significantly increased in methanol-exposed embryos in comparison to controls, particularly in and adjacent to the ventral midline. Apoptosis contributes significantly to methanol neurotoxicity because embryos lacking the cell death genes grim, hid, and reaper have milder CNS defects resulting from methanol exposure than wild-type embryos. Our data suggest that when neurons and glia are severely adversely affected by methanol exposure, the damaged cells are cleared by apoptosis, leading to embryonic death. Thus, the Drosophila embryo may prove useful in identifying and unraveling mechanistic aspects of developmental neurotoxicity, specifically in relation to methanol toxicity.

Animals↗
PubMed1995

Role of formate in methanol-induced exencephaly in CD-1 mice.

Mouse embryos develop exencephaly when dams are exposed by inhalation to high concentrations (> or = 10,000 ppm) of methanol on gestational day 8 (GD8; copulation plug = GD0). The present study examined the role of formate, an oxidative metabolite of methanol, in the development of methanol-induced exencephaly in CD-1 mice and cultured mouse embryos. The pharmacokinetics and developmental toxicity of sodium formate (750 mg/kg by gavage), a 6-hr methanol inhalation (10,000 or 15,000 ppm), or methanol gavage (1.5 g/kg) in pregnant CD-1 mice on GD8 were determined. Gross morphological evaluations for neural tube closure status in embryos or exencephaly in near-term fetuses were performed. Decidual swellings and maternal plasma were analyzed for methanol and formate. The mean (+/- S.E.M.) end-of-exposure plasma methanol concentration was 223 +/- 23 mM following the 6-hr, 15,000 ppm methanol inhalation. There were no changes in blood or decidual swelling formate concentrations under any of the methanol exposure conditions. Peak formate levels in plasma (1.05 +/- 0.2 mM; control 0.5 +/- 0.3 mM) and decidual swelling (2.0 +/- 0.2 mM; control 1.1 +/- 0.2 mM) from pregnant mice (GD8) given sodium formate (750 mg/kg, po) were similar to those observed following a 6-hr methanol inhalation of 15,000 ppm (plasma = 0.75 +/- 0.1 mM; decidual swelling = 2.2 +/- 0.3 mM) but did not result in exencephaly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Acute methanol toxicity in minipigs.

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 validity of this animal model, 12 4-month-old female minipigs (minipig 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, developed within 0.5 to 2.0 hr, and resolved by 52 hr. Average maximum methanol concentrations in plasma, of 3100 +/- 700 (SD), 6200 +/- 2300, and 15,200 +/- 900 micrograms/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 elimination 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 minipigs, 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, toxicologically significant formate accumulation, or metabolic acidosis. 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.

Animals↗
PubMed1995

Comparative toxicokinetics of inhaled methanol in the female CD-1 mouse and Sprague-Dawley rat.

Female CD-1 mice were exposed for 8 hr, both individually and in groups of eight to nine, to 2500, 5000, and 10,000 ppm methanol vapor in a flowthrough exposure chamber. The ventilation of individually exposed mice and the absorption of methanol from the chamber airstream were measured. The extraction of methanol from the airstream and the blood methanol concentration at various time points during and following exposure were determined for the group-exposed mice. The similarity of systemic kinetic parameters (volume of distribution; Michaelis-Menten elimination parameters, Vmax and KM) between inhalation exposure and iv and po routes of administration was verified. Total 8-hr ventilation decreased slightly with increasing exposure concentration. The fraction of inhaled methanol absorbed (0.85 +/- 0.14) did not vary statistically with exposure concentration. Measured ventilation, fractional absorption, and systemic kinetic parameters were combined in a semiphysiologic pharmacokinetic model that yielded accurate predictions of blood methanol concentrations during and after an 8-hr exposure. Model predictions for the mouse were compared to a previously developed inhalation toxicokinetic model for the rat. The comparison demonstrated that at similar methanol vapor concentrations, mice evidenced a two- to threefold higher blood methanol concentration than rats, despite the fact that the apparent Vmax for methanol elimination in the mouse is twofold larger than that in the rat. These data may have significant implications in understanding species differences in methanol-induced teratogenic effects.

Absorption↗
PubMed1997

Time-resolved cutaneous absorption and permeation rates of methanol in human volunteers.

This paper reports on an experimental study of dermal exposure to neat methanol in human volunteers for the purposes of estimating percutaneous absorption rates, permeation kinetics, baseline (pre-exposure) levels of methanol in blood, and inter- and intrasubject variability. A total of 12 volunteers (seven men and five women) were exposed to methanol via one hand for durations of 0 to 16 min in a total of 65 sessions, making this the largest controlled study of percutaneous absorption for this common solvent. In each session, 14 blood samples were collected sequentially and analyzed for methanol. These data were used to derive absorption rates and delivery kinetics using a two compartment model that accounts for elimination and pre-exposure levels. The pre-exposure methanol concentration in blood was 1.7 +/- 0.9 mg 1(-1), and subjects had statistically different mean concentrations. The maximum methanol concentration in blood was reached 1.9 +/- 1.0 h after exposure. Delivery rates from skin into blood lagged exposure by 0.5 h, and methanol continued to enter the systemic circulation for 4 h following exposure. While in vitro studies have reported comparable lag times, the prolonged permeation or epidermal reservoir effect for such miscible solvents has not been previously measured. The mean derived absorption rate, 8.1 +/- 3.7 mg cm-2 h-1, is compatible with that found in the other in vivo study of methanol absorption. Both in vivo absorption rate estimates considerably exceed in vitro estimates. The maximum concentration of methanol in blood following an exposure to one hand lasting approximately 20 min is comparable to that reached following inhalational exposures at a methanol concentration of 200 ppm, the threshold limit value-time weighted average (TLV-TWA). While variability in blood concentrations and absorption rates approached a factor of two, differences between individuals were not statistically significant. The derived absorption and permeation rates provide information regarding kinetics and absorbed dose that can help to interpret biological monitoring data and confirm mathematical models of chemical permeation.

Adult↗