Methanol and formic acid toxicity: biochemical mechanisms.

Metabolism of methanol, methyl ethers, esters and amides give rise to formic acid. This acid is an inhibitor of the mitochondrial cytochrome oxidase causing histotoxic hypoxia. Formic acid is a weaker inhibitor than cyanide and hydrosulphide anions. The body burden of formate in methanol poisoning is high enough to cause acidosis, and other clinical symptoms. Part of the protons can be attributed to formic acid whereas the most significant acid load results from the hypoxic metabolism. The acidosis causes e.g. dilatation of cerebral vessels, facilitation of the entry of calcium ions into cells, loss of lysosomal latency and deranged production of ATP. The latter effect seems to impede parathormone-dependent calcium reabsorption in the kidney tubules. Besides, urinary acidification is affected by formic acid. Its excretion causes continuous recycling of the acid by the tubular cell Cl-/formate exchanger. This sequence of events may partially explain an accumulation of formate in urine. Occupational exposure to vapours of methanol and formic acid can be quantitatively monitored by urinary formic acid determinations. Formic acid toxicity may prove a suitable model for agents causing histotoxic hypoxia.     

American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning

EPIDEMIOLOGY: Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes. MECHANISMS OF TOXICITY: Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells. FEATURES: Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness. MANAGEMENT: For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost. CONCLUSION: The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.     

Toxicological and Metabolic Consequences of Methanol Poisoning

Methanol, when introduced into all mammals, is oxidized into formaldehyde and then into formate, mainly in the liver. Such metabolism is accompanied by the formation of free radicals. In all animals, methanol oxidation, which is relatively slow, proceeds via the same intermediary stages, usually in the liver, and various metabolic systems are involved in the process, depending on the animal species. In nonprimates, methanol is oxidized by the catalase-peroxidase system, whereas in primates, the alcohol dehydrogenase system takes the main role in methanol oxidation. The first metabolite (formaldehyde is rapidly oxidized by formaldehyde dehydrogenase) is the reduced glutathione (GSH)-dependent enzyme. Generated formic acid is metabolized into carbon dioxide with the participation of H 4 folate and two enzymes, 10-formyl H 4 folate synthetase and dehydrogenase, whereas nonprimates oxidize formate efficiently. Humans and monkeys possess low hepatic H 4 folate and 10-formyl H 4 folate dehydrogenase levels and are characterized by the accumulation of formate after methanol intoxication. The consequences of methanol metabolism and toxicity distinguish the human and monkey from lower animals. Formic acid is likely to be the cause of the metabolic acidosis and ocular toxicity in humans and monkeys, which is not observed in most lower animals. Nevertheless, chemically reactive formaldehyde and free radicals may damage most of the components of the cells of all animal species, mainly proteins and lipids. The modification of cell components results in changes in their functions. Methanol intoxication provokes a decrease in the activity and concentration of antioxidant enzymatic as well as nonenzymatic parameters, causing enhanced membrane peroxidation of phospholipids. The modification of protein structure by formaldehyde as well as by free radicals results changes in their functions, especially in the activity of proteolytic enzymes and their inhibitors, which causes disturbances in the proteolytic-antiproteolytic balance toward the proteolytics and enhances the generation of free radicals. Such a situation can lead to destructive processes because components of the proteolytic-antiproteolytic system during enhanced membrane lipid peroxidation may penetrate from blood into extracellular space, and an uncontrolled proteolysis can occur. This applies particularly to extracellular matrix proteins.     

Kinetics and renal effects of formic acid in occupationally exposed farmers

Twelve male farmers (38 ± 14 years of age, mean ± SD) were exposed to 7.3 ± 2.2 mg formic acid/m³ for 8 h in the silage making (mean ± SD,N=12). Each gave urine samples immediately, 15 h and 30 h after the end of the exposure. The excretion of formate was linearly related to the exposure 15 and 30 h after the exposure. Exposure increased renal ammoniagenesis and urinary calcium at 30 h post-exposure. Both biochemical effects may be explained by the interaction of formic acid with the oxidative metabolism of renal tubular cells, as formic acid is a known inhibitor of the cytochrome oxidase. In view of these renal effects, the current hygienic limits may not entirely protect exposed individuals.     

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.     

Simultaneous determination of formic acid and formaldehyde in pharmaceutical excipients using headspace GC/MS

Formic acid and its esters, as well as formaldehyde, are trace impurities that are often present in pharmaceutical excipients. These trace impurities can potentially react with amino and/or hydroxyl groups in drugs to form significant levels of degradants. To select the appropriate excipients for a stable formulation, a gas chromatography/mass spectrometry (GC/MS) method was developed and validated for the rapid screening of trace amounts of residual formic acid, its esters and formaldehyde in pharmaceutical excipients. Samples were dissolved or dispersed in acidified ethanol to convert formic acid and formaldehyde to ethyl formate and diethoxymethane, respectively. Identification was conducted using a GC/MS system under scan mode and quantified using a selected ion monitoring (SIM) mode. Evaluation of the mass spectra of ethyl formate and diethoxymethane in the samples indicated that the method is specific. The limits of quantitation of the method were 0.5 ppm for formic acid and 0.2 ppm for formaldehyde. The precision of the method was demonstrated by the acceptable R.S.D. (相似文献   

Acute airway irritation of methyl formate in mice

Methyl formate (MF) is a volatile solvent with several industrial applications. The acute airway effects of MF were evaluated in a mouse bioassay, allowing the assessment of sensory irritation of the upper airways, airflow limitation of the conducting airways and deep lung (pulmonary) irritation. MF was studied at vapour concentrations of 202–1,168 ppm. Sensory irritation was the only effect observed, which developed slowly over the 30-min exposure period. The potency at steady state was at least 10-fold higher than expected from a hypothetically similar, but non-reactive compound. Methyl formate may be hydrolysed in vivo to formic acid, a potent sensory irritant, and methanol, a low-potent sensory irritant. Hydrolysis may be catalysed by carboxyesterases, and therefore, the role of the esterases was studied using the esterase inhibitor tri-ortho-cresyl phosphate (TOCP). TOCP pre-treatment reduced the irritation response of MF, suggesting that carboxyesterase-mediated hydrolysis plays a role in the irritative effect. However, even after administration of TOCP, MF was considerably more irritating than expected from a quantitative structure–activity relationship (QSAR) model. The slope of the concentration–effect relationship for formic acid was lower than that for the MF in the low-dose range, suggesting that different receptor activation mechanisms may occur, which may include an effect of MF itself, in addition to an effect of formic acid and potentially an effect from formaldehyde.     

The toxicity of inhaled methanol vapors

Methanol could become a major automotive fuel in the U.S., and its use may result in increased exposure of the public to methanol vapor. Nearly all of the available information on methanol toxicity in humans relates to the consequences of acute, rather than chronic, exposures. Acute methanol toxicity evolves in a well-understood pattern and consists of an uncompensated metabolic acidosis with superimposed toxicity to the visual system. The toxic properties of methanol are rooted in the factors that govern both the conversion of methanol to formic acid and the subsequent metabolism of formate to carbon dioxide in the folate pathway. In short, the toxic syndrome sets in if formate generation continues at a rate that exceeds its rate of metabolism. Current evidence indicates that formate accumulation will not challenge the metabolic capacity of the folate pathway at the anticipated levels of exposure to automotive methanol vapor.     

Lack of a role for formaldehyde in methanol poisoning in the monkey.

Methanol was administered either to untreated cynomolgus monkeys or to a folate-deficient cynomolgus monkey which exhibits exceptional sensitivity to the toxic effects of methanol. Marked formic acid accumulation in the blood and in body fluids and tissues was observed. No formaldehyde accumulation was observed in the blood and no formaldehyde was detected in the urine, cerebrospinal fluid, vitreous humor, liver, kidney, optic nerve, and brain in these monkeys at a time when marked metabolic acidosis and other characteristics of methanol poisoning were observed. Following intravenous infusion into the monkey, formaldehyde was rapidly eliminated from the blood with a half-life of about 1.5 min and formic acid levels promptly increased in the blood. Since formic acid accumulation accounted for the metabolic acidosis and since ocular toxicity essentially identical to that produced in methanol poisoning has been described after formate treatment, the predominant role of formic acid as the major metabolic agent for methanol toxicity is certified. Also, results suggest that formaldehyde is not a major factor in the toxic syndrome produced by methanol in the monkey.     

A biologically based dynamic model for predicting the disposition of methanol and its metabolites in animals and humans.

A multicompartment biologically based dynamic model was developed to describe the time evolution of methanol and its metabolites in the whole body and in accessible biological matrices of rats, monkeys, and humans following different exposure scenarios. The dynamic of intercompartment exchanges was described mathematically by a mass balance differential equation system. The model's conceptual and functional representation was the same for rats, monkeys, and humans, but relevant published data specific to the species of interest served to determine the critical parameters of the kinetics. Simulations provided a close approximation to kinetic data available in the published literature. The average pulmonary absorption fraction of methanol was estimated to be 0.60 in rats, 0.69 in monkeys, and 0.58-0.82 in human volunteers. The corresponding average elimination half-life of absorbed methanol through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and 1.7 h. Saturation of methanol metabolism appeared to occur at a lower exposure in rats than in monkeys and humans. Also, the main species difference in the kinetics was attributed to a metabolism rate constant of whole body formaldehyde to formate estimated to be twice as high in rats as in monkeys. Inversely, in monkeys and in humans, a larger fraction of body burden of formaldehyde is rapidly transferred to a long-term component. The latter represents the formaldehyde that (directly or after oxidation to formate) binds to various endogenous molecules or is taken up by the tetrahydrofolic-acid-dependent one-carbon pathway to become the building block of synthetic pathways. This model can be used to quantitatively relate methanol or its metabolites in biological matrices to the absorbed dose and tissue burden at any point in time in rats, monkeys, and humans for different exposures, thus reducing uncertainties in the dose-response relationship, and animal-to-human and exposure scenario comparisons. The model, adapted to kinetic data in human volunteers exposed acutely to methanol vapors, predicts that 8-h inhalation exposures ranging from 500 to 2000 ppm, without physical activities, are needed to increase concentrations of blood formate and urinary formic acid above mean background values reported by various authors (4.9-10.3 and 6.3-13 mg/liter, respectively). This leaves blood and urinary methanol concentrations as the most sensitive biomarkers of absorbed methanol.     

液相色谱-串联质谱法测定人血浆中多潘立酮浓度

目的建立高效液相色谱-串联质谱测定人血浆中多潘立酮(第2代胃动力药)浓度的方法。方法用TC-C18色谱柱,流动相为甲醇(含0.025%甲酸)-1 mmol.L-1甲酸铵溶液(含0.05%甲酸),用梯度洗脱进行分离,流速为1.0 mL.min-1。用正离子化模式,多重反应监测(MRM)扫描方式进行检测定量。结果多潘立酮的线性范围为0.1～50.0 ng.mL-1,日内、日间精密度均小于15%,提取回收率大于80%。结论本方法灵敏、准确、快速,可用于人血浆中多潘立酮浓度的测定和药代动力学研究。     

Studies on the effect of 4-methylpyrazole on methanol poisoning using the monkey as an animal model: With particular reference to the ocular toxicity

Young cynomolgus monkeys (Macaca fascicularis) were chosen as a model to investigate the ocular toxicity in animals poisoned with methanol and treated with 4-methylpyrazole (4-MP).The metabolism of methanol in the monkey was investigated after administration of 4-MP. Plasma levels of methanol, formic acid, 4-MP and 4-hydroxy-MP (4-OH-MP) were determined. After intramuscular injection, 4-MP was rapidly absorbed and depressed the elimination rate of methanol as well as the accumulation of formate in the blood.The results show the same great individual variations in monkeys as in humans regarding the susceptibility to methanol poisoning. Administration of a single dose of 5 g/kg induces a serious intoxication in most monkeys, causing death to some of them. Two monkeys receiving a single dose of 6 g/kg of methanol developed a serious initial inebriation and were treated with 4-MP. These monkeys survived and showed no signs of toxicity on ocular examinations which included ophtalmoscopy and electroretinogram (ERG) recordings.     

Expert opinion: fomepizole may ameliorate the need for hemodialysis in methanol poisoning

Fomepizole is now the antidote of choice in methanol poisoning. The use of fomepizole may also change the indications for hemodialysis in these patients. We have addressed this change in a review of articles on methanol poisonings. Review of the literature (through PubMed) combined with our own experiences from two recent methanol outbreaks in Estonia and Norway. The efficiency of dialysis during fomepizole treatment was reported in only a few reports. One recent study challenged the old indications, suggesting a new approach with delayed or even no hemodialysis. Methanol-poisoned patients on fomepizole treatment may be separated into two categories: 1) The critically ill patient, with severe metabolic acidosis (base deficit >15 mM) and/or visual disturbances should be given buffer, fomepizole and immediate hemodialysis: dialysis removes the toxic anion formate, and assists in correcting the metabolic acidosis, thereby also reducing formate toxicity. The removal of methanol per se is not important in this setting because fomepizole prevents further production of formic acid. 2) The stable patient, with less metabolic acidosis and no visual disturbances, should be given buffer and fomepizole. This treatment allows for the possibility to delay, or even drop, dialysis in this setting, because patients will not develop more clinical features from methanol poisoning when fomepizole and bicarbonate is given in adequate doses. Indications and triage for hemodialysis in methanol poisonings should be modified. Delayed hemodialysis or even no hemodialysis may be an option in selected cases.     

Absorption and elimination of formate following oral administration of calcium formate in female human subjects.

Calcium formate is a water-soluble salt of an essential mineral nutrient with potential for use as a dietary calcium supplement. Formate ion is a product of endogenous and xenobiotic metabolism, but sustained high plasma formate concentrations (such as occur in cases of methanol poisoning) are toxic to the retina and optic nerve. Humans and primates have reduced capacity for formate oxidation compared with rodents and dogs and are thus more sensitive to methanol (and formate) intoxication. To assess the potential for accumulation of formate ion upon repeated administration of calcium formate as a potential dietary calcium supplement, we measured plasma concentrations of formate in 14 adult human subjects before and after oral administration of a single large dose of calcium formate (3900 mg; ca. 3-6 times the anticipated dose for calcium supplementation). Plasma formate concentrations increased briskly from 0.024 +/- 0.008 mM (endogenous formate) to reach C(max) (0.50 +/- 0.04 mM) at 60 min postdose and then declined with a half-life of 59 +/- 7 min. By 225 min postdose, plasma formate concentration had returned to baseline. With such a short half-life, repeated use of calcium formate as a dietary supplement, even three times daily, should not lead to progressive accumulation of formate. These findings are discussed in light of the production of formate by endogenous and xenobiotic metabolism and the kinetics of formate during methanol poisoning.     

氘代内标液质串联法测定血浆中沙丁胺醇的浓度

目的:建立液相-质谱串联法测定人血浆中的沙丁胺醇含量.方法:血浆离心后过玻璃纤维滤膜,经酶解加入氘代沙丁胺醇内标溶液,用C18小柱净化后以3%的氨水甲醇溶液对Oasis MCX小柱进行洗脱,吹干,以0.1%甲酸水溶液-甲醇溶液(95∶5)溶解残余物,用液相质谱串联法测定,以0.1%甲酸乙腈溶液和0.1%甲酸溶液为流动相梯度洗脱.结果:沙丁胺醇在0.25～10.00 μg·kg-1线性关系良好,检出限0.1μg·kg-1.结论:本法灵敏准确、重现性与特异性强、干扰少,可用于人体内沙丁胺醇药动学与生物利用度研究.     

Acute renal injury following methanol poisoning: analysis of a case series

The objective of this paper is to document the prevalence of indicators of acute renal injury in a series of methanol-poisoned patients treated in an intensive care unit and to discuss the possible mechanisms. This is a retrospective analysis of the medical records of 25 consecutive patients admitted to the intensive care unit after severe intentional methanol poisoning. Acute renal impairment was defined as a serum creatinine concentration higher than 177 micro mol/L and/or a urinary output on admission and for the first 24 h below 0.5 ml/kg/h. Clinical pathological signs of acute renal injury were found in 15 patients. In comparison with the 10 other patients taken as control group, the patients who developed renal injury had a lower blood pH value on admission, a higher serum osmolality, and a higher peak formate concentration. Two factors contributing to renal injury could be identified: hemolysis and myoglobinuria. The role of osmotic changes (osmotic nephrosis) or of a direct cytotoxic effect of formic acid remains speculative. Analysis of proteinuria suggests that proximal tubular cells may be preferentially affected. Results of histopathological evaluation of the kidney on a limited sample size (n = 5) were inconclusive but suggestive of possible hydropic changes in the proximal tubule secondary to methanol toxicity. Acute renal injury may be associated with other signs of severity in methanol poisoning, but it is almost always reversible in survivors. Indicators of acute renal injury were identified. The pathophysiology of this acute renal injury is multifactorial and far more complex than shock-related tubular necrosis.     

Role of ethanol metabolism in the alcohol-induced increase in urinary folate excretion in rats

Chronic ethanol use can lead to folic acid deficiency in humans. In rats, acute doses of ethanol produce a marked increase in the urinary excretion of folate which is followed by a decrease in plasma folate levels. To assess the respective roles of ethanol and its metabolism in these effects, five groups of male Sprague-Dawley rats were treated orally as follows: (1) ethanol in four doses of 1 g/kg each at 0, 1, 2 and 3 hr; (2) ethanol as above plus the alcohol dehydrogenase inhibitor 4-methylpyrazole (4-MP) at 50 mg/kg, i.p., 15 min prior to 0 hr; (3) glucose in four isocaloric doses; (4) glucose plus 4-MP as above; and (5) methanol in four doses of 1 g/kg. Total folate levels in the urine peaked in both ethanol- and methanol-treated rats at the same time as the urine alcohol levels (after 6-8 hr) and then declined over the same time course as the alcohol levels. Concurrent administration of 4-MP inhibited the metabolism of ethanol and maintained the increase in urinary folate excretion throughout 24 hr. Ethanol administration produced minor changes in the relative distribution of folate derivatives in the urine, and these changes were not prevented by 4-MP treatment. The urinary levels of formic acid, which is metabolized by folate-dependent processes, were increased by ethanol administration; this increase was prevented by 4-MP. These results suggest that ethanol is not unique among alcohols in increasing urinary folate excretion and that ethanol metabolism plays no role in the increased urinary folate excretion. However, ethanol metabolism contributes to a second effect of ethanol on the folate system, which leads to increased urinary levels of formic acid.     

Multi-residue analysis using liquid chromatography tandem mass spectrometry for detection of 20 coccidiostats in poultry,livestock, and aquatic tissues

In this study, we developed a novel analysis method based on liquid chromatography/tandem mass spectrometry (LC–MS/MS) to allow the simultaneous identification of 20 coccidiostats in eight matrix categories, including the muscles of chicken, swine, cow, and fish as well as chicken eggs, bovine milk, and porcine viscera. In the pretreatment procedure, acetonitrile/methanol (95:5, v/v) containing 1% formic acid, 5 g of sodium acetate, and 6.0 g of anhydrous magnesium sulfate was used for extraction, followed by a clean-up procedure using n-hexane saturated with ACN to facilitate the elimination of analytes from high lipid samples. Chromatographic separations were achieved using a Poroshell 120SB C18 column and operated with a gradient mobile phase system consisting of methanol (with 0.1% formic acid) and 5 mM ammonium formate, and the MS detection was monitored simultaneously. The method was validated in accordance with the Guidelines for the Validation of Food Chemical Methods by the Taiwan Food and Drug Administration. The limit of quantitation among 8 matrices were 0.5–2 ng g⁻¹. The proposed method proved highly effective in detecting the presence of targeted veterinary drugs, providing a high degree of precision and accuracy over a broad range of matrices.     

Formic acid and methanol concentrations in death investigations

Methanol ingestion results in the formation of formic acid, a toxic metabolite that can cause metabolic acidosis. Methanol toxicity is therefore dependent on the amount of methanol ingested, the nature of treatment received, elapsed time since ingestion, and the accumulation of formic acid. Both methanol and formic acid concentrations are determined at this laboratory using headspace gas chromatography. An examination of 12 fatalities attributed to methanol poisoning is presented. Six individuals were found deceased, and their postmortem methanol and formic acid concentrations ranged from 84 to 543 mg/dL and 64 to 110 mg/dL, respectively. In the other six individuals, hospital treatment such as bicarbonate, ethanol infusion, and hemodialysis was administered. Antemortem methanol and formic acid concentrations ranged from 68 to 427 mg/dL and 37 to 91 mg/dL, respectively, whereas corresponding postmortem methanol and formic acid levels ranged from undetectable to 49 mg/dL and undetectable to 48 mg/dL, respectively. Hospital treatment of formic acid toxicity resulted in significantly reduced postmortem methanol and formic acid concentrations. Furthermore, the toxicological relevance of nine methanol-positive cases where postmortem methanol concentrations ranged from 3 to 142 mg/dL, with corresponding formic acid levels of less than 10 mg/dL, is discussed.     

Formic acid excretion in rats and mice exposed to bromodichloromethane: a possible link to renal tubule cell proliferation in long-term studies

Male F344 rats exposed to bromodichloromethane (BDCM) by gavage at 50 or 100 mg/kg/day for 5 days a week for 28 days excreted large amounts of formic acid in their urine, which was accompanied by a change in urinary pH. Male B6C3F1 mice exposed to BDCM at 25 or 50 mg/kg/day for 5 days a week for 28 days also excreted increased amounts of formic acid in their urine. In rats, formate excretion was dose and time dependant, being markedly elevated after four doses and remaining at that level after 3 weeks of dosing at 100 mg/kg/day BDCM, while at 50 mg/kg/day there was some suggestion of a decline after 3 weeks. In contrast, in mice formate excretion did not start to a major extent until 3 weeks of dosing, with the biggest response at 4 weeks. There was no increase in clinical chemistry markers of liver or kidney injury in either rats or mice following 28-day exposure to BDCM. However, morphological examination of the kidneys showed some mild renal tubule injury in two out of five rats exposed to 100 mg/kg/day BDCM. This was associated with a marked increase in cell proliferation in the renal cortex of all rats exposed to 100 mg/kg/day. No increase in cell proliferation was seen in the renal cortex of rats exposed to BDCM at 50 mg/kg/day, or in mice exposed to 25 or 50 mg/kg/day BDCM for 28 days. Long-term exposure to formic acid is known to cause kidney damage, suggesting that excretion of this acid may be a contributory factor to the increase in cell proliferation and kidney damage seen in the longer-term studies with BDCM.