Blood Methanol Research Articles

Estudio de un brote de intoxicación por alcohol metílico en Santa Fe de Bogotá, 1994

The National Institute of Legal Medicine and Forensic Science's Toxicology Laboratory (Laboratorio de Toxicología del lnstituto Nacional de Medicina Legal y Ciencias Forenses, INML y CF), observed an increase in positive samples for methanol in blood from medicolegal necropsies performed in June, 1994. Thus an epidemiological study was designed to establish diagnosis, to identify riskfactors and to control and prevent new outbreaks. questionnaire. Cases of fatal methyi poisoning (FMP) were defined as being those deaths which ocurred during June, 1994, whose necropsy was carried out at INML y CF, having methanol concentrations greater than 30 mg/dL and whose report established methanol poisoning as the basic cause of death. Fourteen peoplediedfrom FMP, the total number of cases being amongst destitute people. The 'scan' statistical function (p=0,004) showed that the excess of deaths in June, 1994, was statistically significant in relation to previous months. Twelve of the cases received medical attention and four were diagnosed as suffering from FMP before theirdeaths. All cases presented methanol concentrations in blood between 43 and 190.4 mg/dL. This is the first methanol poisoning conglomeration amongst destitute people which has been described in the country and has shown the necessity of establishing public health policies directed towards protection of destitute people and the prevention of methanol poisoning.

Highly sensitive gas chromatographic analysis of ethanol in whole blood, serum, urine, and fecal supernatants by the direct injection method

A highly sensitive, reproducible, and rapid gas chromatographic method for ethanol determination in various biological specimens (human whole blood, serum, urine, and fecal supernatants) was developed. The method involves direct injection of the biological specimen into the gas chromatograph, without any pretreatment. Contamination of the gas chromatographic column with nonvolatile material was prevented by the use of a glass liner in the injector. This liner, which acted as a precolumn, was partly filled with small glass beads. Injection was performed in between the glass beads. More than 50 injections of the various biological specimens could be done before the liner had to be replaced by a new one. This injection technique between glass beads allows direct injection of large sample volumes up to 10 microL without disturbing the gas chromatographic separation. Injection of these large sample volumes made the method very sensitive. The detection limit for ethanol amounted to 0.1 mg/L (2 mumol/L) when using an injection volume of 5 microL. Attention has also been paid to simultaneously monitoring ethanol, methanol, acetaldehyde, and acetone in blood and urine of control subjects.

Perinatal methanol exposure in the rat. I. Blood methanol concentration and neural cell adhesion molecules.

Although the acute toxicity of methanol is well documented, few studies have addressed the consequences of perinatal exposures to the low concentrations that are expected to arise from its proposed use as a component of automobile fuel. This report describes the general research design of a series of studies, the effects of methanol exposures on blood concentrations in dams and neonates, and indices of brain development. Four cohorts of Long-Evans pregnant rats, each cohort consisting of an exposure (n = 12) and a control (n = 12) group, were exposed whole-body to 4500 ppm methanol vapor or air for 6 hr daily beginning on Gestation Day 6. Both dams and pups were then exposed through Postnatal Day 21 (PND 21). Blood methanol concentrations determined by gas chromatography from samples obtained immediately following a 6-hr exposure reached approximately 500-800 micrograms/ml in the dams during gestation and lactation. Average concentrations for pups attained levels about twice those of the dams. Selected offspring from Cohort 4 were exposed for one additional 6-hr session at ages that extended out to PND 52. Regression analyses showed that the blood methanol concentrations of the pups declined until about PND 48, at which time their levels approximated those of their dams. Such pharmacokinetic differences might increase the risks posed to developing organisms. Light-microscopic analysis showed no significant abnormalities in the brains of the methanol-treated animals. However, assays of neural cell adhesion molecules (NCAMs) in brains of pups sacrificed on PND 4 showed staining for both the 140 and the 180 kDa isoforms to be less intense in the cerebellum of exposed animals. NCAM differences were not apparent in animals sacrificed 15 months after their final exposure.

Use of Intrauterine Microdialysis to Investigate Methanol-Induced Alterations in Uteroplacental Blood Flow

Methanol is teratogenic in rodents; it has been postulated that this teratogenicity may be mediated in part by conceptal hypoxia. To construct a model to predict conceptal risk following maternal methanol exposure, conceptal disposition of methanol must be determined and any effects of such exposure on blood flow must be quantitated. In the present study, these toxicokinetic and toxicodynamic parameters were evaluated byin vivointrauterine microdialysis. Microdialysis probes were inserted into the uteri of Gestational Day (gd) 20 rats; methanol was administered as either an iv bolus (100 or 500 mg/kg) or infusion (100 or 1000 mg/kg/hr). In separate experiments, methanol (100 or 500 mg/kg) and3H2O (20 μCi/kg) were administered iv to gd 20 and 14 rats and gd 18 mice. In both experiments, maternal blood and uterine microdialysate were collected and analyzed for methanol or3H2O content. The methanol concentration–time data were consistent with saturable maternal elimination and apparent first-order transfer between maternal and conceptal compartments; at distribution equilibrium, conceptal methanol concentrations exceeded those in the dam by approximately 25%. The initial rate of conceptal permeation of methanol was proportional to the reciprocal of maternal blood methanol concentration (r2= 0.910). Methanol also reduced significantly the rate of3H2O uptake into the conceptus in a concentration-dependent fashion in gd 14 and 20 rats and gd 18 mice. These data indicate that methanol may decrease uteroplacental blood flow, decreasing methanol presentation to the conceptus and possibly producing conceptal hypoxia.

Laboratory testing for recent alcohol consumption: comparison of ethanol, methanol, and 5-hydroxytryptophol

The ratio of 5-hydroxytryptophol to 5-hydroxyindole-3-acetic acid (5HTOL/5HIAA) in urine was compared with concentrations of ethanol and methanol as a way to monitor recent alcohol consumption. During detoxification of alcohol-dependent subjects, ethanol persisted longer in urine than in breath or plasma. Blood and urinary methanol remained increased for 2-6 h after blood ethanol had returned to background concentrations, whereas 5HTOL/5HIAA remained increased for 6-15 h. In healthy volunteers who had ingested alcohol (range 3-98 g) the previous afternoon or evening, 87% (for men) and 59% (for women) of all drinking occasions exceeding 7 g of alcohol were identified by an increased 5HTOL/5HIAA in the first morning urine void. This compared with 32% and 12%, respectively, identified by analysis of ethanol (>200 micromol/L). No gender difference in the excretion pattern of 5HTOL/5HIAA was seen. The results demonstrate that 5HTOL/5HIAA provides a specific and more sensitive method to detect recent alcohol consumption than does ethanol or methanol.

Blood and Urine Bioindicators for Methanol Exposure: Effect of Chilled and Frozen Sample Storage

Abstract Measurements of methanol concentrations in blood and urine may be used as bioindicators of methanol exposure that account for all exposure pathways. These measurements will be practical if the integrity of samples from the time of collection to the time of analysis can be maintained. This study was designed to test the stability of methanol in blood and urine samples stored at 4° and −20°C for various periods of time up to 7 months. Methanol recoveries of the stored blood samples were found to fit a first-order decay model, with the best estimates for the half-life of methanol in chilled and frozen blood of 114 ± 14 and 240 ± 58 days, respectively. A half-life of 562 ± 145 days is estimated for chilled and frozen urine. These long half-lives enhance the utility of methanol bioindicators. While freezing increased the recovery in blood, it also decreased the reproducibility of results. Thus, refrigeration of samples is recommended if the analysis will be completed within about a month of sample collection, and freezing of samples is suggested otherwise. For blood, sample preservation was not enhanced using an all-glass storage system, and a conventional sampling container yielded equivalent results. Batterman, S.A.; Xiao, H.; Franzblau, A.: Blood and Urine Bioindicators for Methanol Exposure: Effect of Chilled and Frozen Sample Storage. Appl. Occup. Environ. Hyg. 11(1):25–29; 1996.

Methanol inhalation: site and other factors influencing absorption, and an inhalation toxicokinetic model for the rat.

This investigation was conducted to identify the site and characteristics of methanol absorption and to develop an inhalation model relating methanol absorption, blood concentration, and elimination. Rats were exposed to methanol in chambers that allowed measurement of methanol uptake, ventilation, and blood concentrations; anesthetized rats with a tracheal cannula were examined to determine tracheal concentrations. In separate experiments, methanol exposed rats received an iv methanol bolus to examine the effect of blood methanol on ventilation and absorption; ventilation also was manipulated by CO(2) or pentobarbital to assess the effect of ventilation rate on methanol absorption. These data were combined to construct a semi-physiologic model of methanol uptake. Only 1-3 percent of inhaled methanol reached the trachea, primarily from systemic methanol partitioning into the trachea; blood methanol did not alter methanol absorption. Manipulation of ventilation and application of the pharmacokinetic model indicated that ventilation was less significant than environmental methanol concentration in determining the fraction of inhaled methanol absorbed, although both parameters were important determinants of the total mass absorbed. These data indicate that methanol uptake is a complex process that depends upon several parameters. Despite these complexities, a relatively simple semi-physiologic model was capable of describing methanol uptake over a wide range of exposure concentrations in the rat.

Ventilation of Ambulatory Rats Exposed to Methanol Vapor in a Flow-Through Exposure System: Measurement and Input to Toxicokinetic Models

AbstractVentilation parameters (minute ventilation, V; tidal volume, Vt; and breathing frequency, f) of female Sprague-Dawley rats were measured during an 8-h exposure to methanol vapor at concentrations of 1000, 5000, 10, 000, 15, 000 and 20, 000 ppm. Rats were exposed individually in a flow-through chamber that permitted simultaneous measurement of ventilation, methanol extraction from the airstream by the animal, and blood methanol concentration. Compared to the whole-body plethysmography with nose-only exposure (WBP) system, the total ventilation of rats in this study was approximately half; the Vt was approximately the same, but f was about 50% lower than reported in WBP exposed rats. The hourly ventilation decreased slightly with increasing blood methanol concentration up to 2000 mg/L; at concentrations exceeding 2000 mg/L, the hourly ventilation decreased more significantly. The exposure system method studied simultaneously yielded information on the extraction of methanol from the airstream, effi...

Comparative Toxicokinetics of Inhaled Methanol in the Female CD-1 Mouse and Sprague-Dawley Rat

Comparative Toxicokinetics of Inhaled Methanol in the Female CD-1 Mouse and Sprague-Dawley Rat. Perkins, R. A., Ward, K. W., and Pollack, G. M. (1995). Fundam. Appl. Toxicol. 28, 245-254.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.

Assessment of Offspring Development and Behavior Following Gestational Exposure to Inhaled Methanol in the Rat

Assessment of Offspring Development and Behavior Following Gestational Exposure to Inhaled Methanol in the Rat. Stanton, M. E., Crofton, K. M., Gray, L. E., Gordon, C. J., Boyes, W. K., Mole, M. L., Peele, D. B, and Bushnell, P. J. (1995). Fundam. Appl. Toxicol. 28, 100-110. The prospect of widespread human exposure associated with its use as an alternative fuel has sparked concern about the toxic potential of inhaled methanol (MeOH). Previous studies have revealed congenital malformations in rats following inhaled MeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5, 727-736) but these studies did not include postnatal behavioral assessment. In the present study, pregnant Long-Evans rats were placed in exposure chambers containing 15,000 ppm MeOH or air for 7 hr/day on Gestational Days (GD) 7-19. The total alveolar dose of methanol was estimated at about 6.1 g/kg/day, for a total dose of about 42.7 g/kg for the entire study. Maternal body weights were recorded daily and blood methanol concentrations were determined at the end of exposure on GD 7, 10, 14, and 18. Following birth (Postnatal Day 0 [PND 0]), a number of tests were performed at various points in development, including: offspring mortality and body wt (PND 1, 3), motor activity (PND 13-21, 30, 60), olfactory learning (PND 18), behavioral thermoregulation (PND 20-21), T-maze learning (PND 23-24), acoustic startle response (PND 24, 60), reflex modification audiometry (PND 60), pubertal landmarks (PND 31-56), passive avoidance (PND 72), and visual-evoked potentials (PND 160). Maternal blood MeOH levels, measured from samples taken within 15 min after removal from the exposure chamber, declined from about 3.8 mg/ml on the first day of exposure to 3.1 mg/ml on the 12th day of exposure. MeOH transiently reduced maternal body wt (4-7%) on GD 8-10, and offspring BW (5%) on PND 1. No. other test revealed significant effects of MeOH. Prenatal exposure to high levels of inhaled MeOH appears to have little effect on this broad battery of tests beyond PND 1 in the rat.

Comparative Toxicokinetics of Methanol in the Female Mouse and Rat

Comparative Toxicokinetics of Methanol in the Female Mouse and Rat. Ward, K. W., Perkins, R. A., Kawagoe, J. L., and Pollack, G. M. (1995). Fundam. Appl. Toxicol. 26, 258-264. The toxicokinetics of methanol in female CD-1 mice and Sprague-Dawley rats were examined to explore the possibility of species differences in the disposition of the compound. Mice received a single dose of 2.5 g/kg methanol either po (by gavage) or iv (as a 1-min infusion). Rats received a single oral dose of 2.5 g/kg methanol. As expected, the disposition of methanol was nonlinear in both species. Data obtained after iv administration of methanol to mice were well described by a one-compartment model with Michaelis-Menten elimination. Blood methanol concentration-time data after oral administration could be described by a one-compartment (mice) or two-compartment (rats) model with Michaelis-Menten elimination from the central compartment and biphasic absorption from the gastrointestinal tract. Kinetic parameters ( V max for elimination, apparent volume of the central compartment [ V c], first-order rate constants for intercompartmental transfer [ k 12 and k 21], and first-order absorption rate constants for fast [ k AF] and slow [ k AS] absorption processes) were compared between species. When normalized for body weight, mice evidenced a higher maximal elimination rate than rats ( V max = 117 ± 3 mg/hr/kg vs 60.7 ± 1.4 mg/hr/kg for rats). The contribution of the fast absorption process to overall methanol absorption also was larger in the mouse than in the rat.

Postmortem Diffusion of Alcohol from the Stomach

We explored postmortem ethanol diffusion from the stomach using a human cadaver model with multiple blood site sampling. In all, 400 ml of alcohol solution (5%, 10%, 20%, or 40% methanol and ethanol weight/volume in water) was introduced into the stomach by oesophageal tube. Blood methanol concentrations correlated with ethanol concentrations (methanol range, 1-676 mg%; ethanol range, 1-531 mg%; r = 0.9973). The pattern of ethanol diffusion showed marked between-case variability. Typically, concentrations were highest in pericardial fluid and, in decreasing order, in left pulmonary vein, aorta, left heart, pulmonary artery, superior vena cava, inferior vena cava, right heart, right pulmonary vein, and femoral vein. Diffusional flux was broadly proportional to the concentration of ethanol used. It was time-dependent (as assessed by 24-h and 48-h sampling) and markedly inhibited by refrigeration at 4 degrees C. After gastric instillation of 400 ml of 5% solution for 48 h at room temperature in paired cadavers, ethanol concentrations (mg%) were as follows: pericardial fluid 135, 222; aorta 50, 68; left heart 77, 26; right heart 41, 28; femoral vein 0. Using a 10% solution, ethanol concentrations (mg%) were as follows: pericardial fluid 401, 255; aorta 129, 134; left heart 61, 93; right heart 31, 41; femoral vein 5, 7. Introducing 50 ml of 10% alcohol solution into the oesophagus after oesophagogastric junction ligation produced similar aortic blood ethanol concentrations. This suggests that postmortem gastrooesophageal reflux and diffusion from the oesophagus is the mechanism of artefactual elevation of aortic blood ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative Toxicokinetics of Methanol in the Female Mouse and Rat

The toxicokinetics of methanol in female CD-1 mice and Sprague-Dawley rats were examined to explore the possibility of species differences in the disposition of the compound. Mice received a single dose of 2.5 g/kg methanol either po (by gavage) or iv (as a 1-mm infusion). Rats received a single oral dose of 2.5 g/kg methanol. As expected, the disposition of methanol was nonlinear in both species. Data obtained after iv administration of methanol to mice were well described by a one-compartment model with Michaelis-Menten elimination. Blood methanol concentration-time data after oral administration could be described by a one compartment (mice) or two-compartment (rats) model with Michaelis-Menten elimination from the central compartment and biphasic absorption from the gastrointestinal tract Kinetic parameters (Vmax for elimination, apparent volume of the central compartment [Ve first-order rate constants for intercompartmental transfer [k12 and k21 and first-order absorption rate constants for fast [kAF] and slow [kAS] absorption processes) were compared between species. When normalized for body weight, mice evidenced a higher maximal elimination rate than rats (Vmax=117±3 mg/hr/kg vs 60.7±1.4 mg/hr/kg for rats). The contribution of the fast absorption process to overall methanol absorption also was larger in the mouse than in the rat.

Role of retinal metabolism in methanol‐induced retinal toxicity

Methanol is a toxicant that causes systemic and ocular toxicity after acute exposure. The folate-reduced (FR) rat is an excellent animal model that mimics characteristic human methanol toxic responses. The present study examines the role of the methanol metabolites formaldehyde and formate in the initiation of methanol-induced retinal toxicity. After a single oral dose of 3.0 g/kg methanol, blood methanol concentrations were not significantly different in FR rats compared with folate-sufficient (FS) (control) rats. However, FR rats treated with 3.0 g/kg methanol displayed elevated blood (14.6 mM) and vitreous humor (19.5 mM) formate levels and abnormal electroretinograms (loss of b-wave) 48 h postdose. FR rats pretreated with disulfiram (DSF) prior to 3.0 g/kg methanol treatment failed to display these symptoms. Formaldehyde was not detected in blood or vitreous humor with or without DSF treatment, suggesting that formate is the toxic metabolite in methanol-induced retinal toxicity. Additionally, creating a blood formate profile (14.2 mM at 48 h) similar to that observed in methanol-treated rats by iv infusion of pH-buffered formate does not alter the electroretinogram as is observed with methanol treatment. These data suggest that intraretinal metabolism of methanol is necessary for the formate-mediated initiation of methanol-induced retinal toxicity.

Methanol detoxification by enzyme-loaded erythrocytes.

Alcohol oxidase (AlOx) from Pichea pastoris (a methylotrophic yeast) was encapsulated into human and murine erythrocytes up to 2 units/ml of packed cells. This enzyme has a much higher affinity for methanol than for ethanol, thus making the loaded erythrocytes useful cellular bioreactors able to catabolize methanol. Enzyme-loaded erythrocytes showed an increased rate of the hexose-monophosphate-shunt activity and a significant methaemoglobin production. However, the in vivo survival of these cells does not seem to be significantly affected by methanol catabolism. In vivo, mice receiving AlOx-loaded erythrocytes were able to keep the blood methanol concentrations below values that were about 50% of those found in mice receiving unloaded cells and similar amounts of methanol. Thus AlOx-loaded erythrocytes may add an important contribution to the detoxification protocol against methanol poisoning.

Toxicokinetics of Intravenous Methanol in the Female Rat

Toxicokinetics of Intravenous Methanol in the Female Rat. Pollack, G. M., Brouwer, K. L. R., and Kawagoe, J. L. (1993). Fundam. Appl. Toxicol. 21, 105-110.The toxicokinetics of intravenously administered methanol were examined in female Sprague-Dawley rats. Animals received a single administration of 100, 500, or 2500 mg methanol/kg; the two lower doses were administered as a bolus, while the high dose was administered over 1.5 min. A small (approximately 3%) but statistically insignificant (p > 0.1) degree of transpulmonary methanol extraction, expressed as the fractional arterial-venous difference in concentration, was observed after administration of 250 mg methanol/kg. The elimination of methanol from the systemic circulation was markedly nonlinear, suggestive of a significant capacity-limited route of elimination. A single set of kinetic parameters (apparent distributional volume of the central compartment [Vc], intercompartmental transfer rate constants [k12 and k21], and Vmax and Km for elimination) described the blood methanol concentration-time data from rats receiving the 100 and 500 mg/kg doses. Blood methanol concentrations declined much more rapidly in animals receiving the 2500 mg/kg dose than would be predicted from the kinetic parameters derived from the other two experimental groups. The data from the 2500 mg/kg group could be described adequately by a kinetic model incorporating parallel first-order and saturable elimination processes. A portion of this apparent linear elimination pathway was due to renal excretion of the unchanged alcohol. The presence of both linear and nonlinear elimination pathways for methanol may have implications regarding high-dose to low-dose toxicologic extrapolations.

The developmental toxicity of inhaled methanol in the CD‐1 mouse, with quantitative dose—response modeling for estimation of benchmark doses

The developmental toxicity of the alternative motor vehicle fuel methanol was assessed in mice by the inhalation route. Pregnant CD-1 mice were exposed to 1,000, 2,000, 5,000, 7,500, 10,000, or 15,000 ppm methanol for 7 hr/day on days 6-15 of gestation. Sham-exposed controls were exposed to filtered air under similar conditions. Additional control groups were left in their home cages either unhandled or food-deprived for 7 hr/day to match the food deprivation experienced by the exposed mice. Dams were observed twice daily and weighed on alternate days during the exposure period. Blood methanol concentrations were determined in some mice on gestation days 6, 10, and 15. On day 17, the remaining mice were weighed and killed and the gravid uteri removed. Implantation sites, live and dead fetuses and resorptions were counted, fetuses were examined externally and weighed as a litter. Half of each litter was examined for skeletal morphology and the other half of each litter was examined for internal soft tissue anomalies. One dam died in each of the 7,500, 10,000, and 15,000 ppm methanol exposure groups, but no dose-response relationship was evident for maternal death. The sham-exposed and food-deprived controls as well as all methanol exposed dams gained less weight than did unexposed dams fed ad libitum, but methanol did not exacerbate this effect. Significant increases in the incidence of exencephaly and cleft palate were observed at 5,000 ppm and above, increased embryo/fetal death at 7,500 ppm and above (including an increasing incidence of full-litter resorptions), and reduced fetal weight at 10,000 ppm and above. A dose-related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2,000 ppm and above. Thus, the NOAEL for the developmental toxicity in this study was 1,000 ppm. A log-logistic dose response model was applied to the incidence data for exencephaly, cleft palate, resorption and cervical rib, and maximum likelihood estimates (MLEs) and benchmark dosages (BDs, the lower 95% confidence interval of the MLEs) corresponding to 1% and 5% added risk above background were calculated. The MLE for 5% added combined risk of having either exencephaly or cleft palate or being resorbed was 3667 ppm, and the corresponding BD was 3,078 ppm. For cervical rib, the 5% added risk values for the MLE and BD were 824 and 305 ppm, respectively. The BDs for 1% added risk were 1915 ppm for exencephaly, cleft palate or resorption, and 58 ppm for cervical rib.(ABSTRACT TRUNCATED AT 400 WORDS)

KINETICS OF ETHANOL AND METHANOL IN ALCOHOLICS DURING DETOXIFICATION

We investigated the kinetics of ethanol and methanol in 20 dependent alcoholics (16 men and four women) during the first 24 hr after admission to hospital for detoxification. The blood-ethanol concentration (BEC) on admission ranged from 238 to 489 mg/dl (mean 386 mg/dl). The mean rate of ethanol disappearance from the blood was 23 mg/dl/hr with a spread from 13 to 36 mg/dl/hr. The concentrations of methanol in blood at the start of detoxification ranged from 0.16 to 2.8 mg/dl (mean 1.15 mg/dl) and these levels remained more or less unchanged until the BEC had dropped below 30 mg/dl. The concentrations of ethanol and methanol in blood at the start of detoxification were not correlated (r = 0.032, P > 0.05). The results of this study do not support the notion that the metabolism of methanol in chronic alcoholics proceeds independently of the prevailing BEC. We found a three-fold difference in the rate of disappearance of ethanol from blood in alcohol-dependent subjects.

Physiologically based pharmacokinetic model for methanol in rats, monkeys, and humans

The pharmacokinetics of methanol and formate were characterized in male Fischer-344 rats and rhesus monkeys exposed to methanol vapor concentrations between 50 and 2000 ppm for 6 hr. End-of-exposure blood methanol concentrations were not directly proportional to the atmospheric concentration. The methanol exposures did not cause an elevation in blood formate concentrations. After an intravenous dose of [ 14C]methanol in rats, metabolism, exhalation, and renal excretion contributed 96.6, 2.6, and 0.8%, respectively, to the elimination of blood methanol concentrations. These values and the calculated renal methanol extraction efficiency (0.007) are nearly identical to those for humans after low doses of methanol. A physiologically based pharmacokinetic model was developed to simulate the in vivo data. In order to simulate the observed blood methanol concentrations in the inhalation studies in rats, a double pathway for methanol metabolism to formaldehyde was used. One path used rodent catalase K m and V max values and the other used a smaller K m and V max to simulate an enzyme with a higher affinity and lower capacity. The lack of proportionality observed in end-of-exposure blood methanol concentrations may be due to saturation of an enzyme with higher affinity and lower capacity than catalase. The physiologically based pharmacokinetic model was modified to simulate the monkey data and was scaled-up for humans. In order to simulate the monkey blood methanol concentrations, the use of rodent catalase parameters for methanol metabolism was required. This finding suggests that primates and rodents may be similar in the initial step of methanol metabolism after low methanol doses. Previously published human urinary methanol excretion data was successfully simulated by the model. The models were used to predict the atmospheric methanol concentration range over which the laboratory species exhibit quantitative similarities with humans. Below 1200 ppm, all three species exhibit similar end-of-exposure blood methanol concentrations and a linear relationship between atmospheric and blood methanol concentrations. At higher atmospheric concentrations, external and internal methanol concentrations increase disparately, suggesting that delivered dose rather than exposure concentration should be used in interpreting data from high-dose studies.

Lack of blood formate accumulation in humans following exposure to methanol vapor at the current permissible exposure limit of 200 ppm.

Accumulation of formate, the putative toxic metabolite of methanol, in the blood and the relationship between pulmonary intake and blood methanol concentration were investigated in six human volunteers following a 6-hr exposure to 200 ppm methanol (the current Occupational Safety and Health Administration 8-hr time-weighted average permissible exposure limit). At the end of a 6-hr exposure to 200 ppm methanol at rest, the blood methanol concentration was increased from a mean of 1.8 micrograms/mL to 7.0 micrograms/mL. Under light exercise, the total amount of methanol inhaled during the 6-hr exposure period was 1.8 times that inhaled at rest. However, no statistically significant increase in blood methanol concentration was observed under exercise: the concentrations averaged 8.1 micrograms/mL. Formate did not accumulate in the blood above its background level following the 6-hr exposures to 200 ppm methanol whether subjects were exposed at rest or during exercise. Unlike the data collected from epidemiologic studies, the authors' results were obtained under well-controlled methanol exposure conditions and by using appropriate dietary restrictions. The data show that (1) the biological load of methanol would be the same regardless of whether workers are engaged in light physical activity when they are exposed to methanol vapors below 200 ppm and (2) the formate that is associated with acute methanol toxicities in humans does not accumulate in blood when methanol exposure concentrations are below 200 ppm.