Formic Acid Excretion Research Articles

The effect of trichloroethylene metabolites on the hepatic vitamin B12-dependent methionine salvage pathway and its relevance to increased excretion of formic acid in the rat

The industrial solvent trichloroethylene (TCE) and its two major metabolites trichloroethanol (TCE-OH) and trichloroacetic acid (TCA) cause formic aciduria in male F344 rats. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE (16mk/kg, po), completely prevented formic aciduria, but had no effect on formic acid excretion produced by TCA (8 or 16mg/kg, po), suggesting TCA may be the proximate metabolite producing this response. Dow and Green reported an increase in the concentration of 5-methyltetrahydrofolate (5-MTHF) in the plasma of rats treated with TCE-OH, suggesting a block in the cycling of 5-MTHF to tetrahydrofolate (THF). This pathway is under the control of the vitamin B12-dependent methionine salvage pathway. We therefore treated rats with three daily doses of methylcobalamin (CH3Cbl) or hydroxocobalamin (OHCbl), a cofactor for methionine synthase, or L-methionine, followed by TCE (16mg/kg) to determine if they could alleviate the formic aciduria. These pretreatments only partially reduced the excretion of formic acid in the urine. Although prior treatment with S-adenosyl-L-methionine had no effect on formic acid excretion. Consistent with these findings, the activity of methionine synthase in the liver of TCE-treated rats was not inhibited. Transcriptomic analysis of the liver-identified nine differential expressed genes, of note, was downregulation of Lmbrd1 involved in the conversion of vitamin B12 into CH3Cbl, a cofactor for methionine synthase. Our findings indicate that the formic aciduria produced by TCE-OH and TCA may be the result of a block in the recycling of 5-MTHF to THF, the effect on the methionine salvage pathway being a secondary response following acute exposure.

Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure.

Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500mg/kg/day) or TCE-OH at (100mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for metabolism via glutathione conjugation.

Attenuation of subchronic formaldehyde inhalation toxicity with oral administration of glutamate, glycine and methionine

Inhalation exposure of outbred female white rats (initial age about 4 months) to formaldehyde vapours (12.8±0.69mg/m3) 4h per day, 5 days per week during 10 weeks induced statistically significant changes in some indices characterizing differential WBC count, functional status of the central nervous system and liver, redox and porphyrin metabolisms, bone marrow micronuclei count as well as free amino acid spectrum of the blood serum. The development of intoxication was accompanied by increased urinary excretion of formaldehyde, formic acid and methanol. Daily oral administration of glutamate (150–180mg), glycine (12mg) and methionine (50mg) in combination rendered all of the formaldehyde's toxic effects reduced. This administration also caused a significant increase in the ratio between the rates of excretion of formic acid and non-metabolized formaldehyde. This shift supposedly reflects activation of oxidative detoxifying biotransformation of formaldehyde. Taking into consideration that the combination of amino acids used in this study proved innocuous in protectively effective doses, the administration in this combination may be recommended to humans exposed to high levels of formaldehyde in workplace or ambient air.

Trichloroethylene-induced formic aciduria: Effect of dose, sex and strain of rat

The industrial solvent trichloroethylene (TCE) has been reported to increase the excretion of formic acid in the urine of male Fischer 344 (F-344) rats following large oral doses. We have examined the dose–response relationship for formic aciduria in male and female Fischer 344 rats, the effect of some known metabolites of TCE and examined the response in male Wistar rats to help understand its relevance to renal toxicity. We report that doses of TCE as low as 8mg/kg for 3 days to both male and female F344 rats produced formic aciduria. The formic aciduria was time-dependent being more marked after 3 doses compared to one dose in male F344 rats and to a lesser extent in female F344 rats. TCE administration to male Wistar rats produced less formic aciduria than in male F344 rats, indicating a strain difference in response. As TCE is primarily metabolised by cytochrome P450 2E1, Wistar rats were administered inducers of cytochrome P450 2E1 followed by TCE, this increased formic acid excretion to a concentration similar to that observed in male F344 rats, indicating a role for P450. Administration of the major metabolites of TCE, trichloroethanol and trichloroacetic acid to male F344 rats also produced a marked and sustained formic aciduria, while the metabolite of TCE formed via glutathione conjugation had no effect on formic acid excretion. The mechanism whereby this response occurs is currently not understood, but the formic acid excreted is not a metabolite of TCE, but appears to be due to interference with the metabolic utilisation of formate by a down stream metabolite of TCE. Over the three days of the studies no histopathological evidence of kidney toxicity was observed in F344 rats given TCE, indicating that the perturbation of formate metabolism does not lead to acute renal injury.

Increased formic acid excretion and the development of kidney toxicity in rats following chronic dosing with trichloroethanol, a major metabolite of trichloroethylene.

The chronic toxicity of trichloroethanol, a major metabolite of trichloroethylene, has been assessed in male Fischer rats (60 per group) given trichloroethanol in drinking water at concentrations of 0, 0.5 and 1.0 g/l for 52 weeks. The rats excreted large amounts of formic acid in urine reaching a maximum after 12 weeks ( approximately 65 mg/24 h at 1 g/l) and thereafter declining to reach an apparent steady state at 40 weeks (15-20 mg/24 h). Urine from treated rats was more acidic throughout the study and urinary methylmalonic acid and plasma N-methyltetrahydrofolate concentrations were increased, indicating an acidosis, vitamin B12 deficiency and impaired folate metabolism, respectively. The rats treated with trichloroethanol developed kidney damage over the duration of the study which was characterised by increased urinary NAG activity, protein excretion (from 4 weeks), increased basophilia, protein accumulation and tubular damage (from 12 to 40 weeks), increased cell replication (at week 28) and evidence in some rats of focal proliferation of abnormal tubules at 52 weeks. It was concluded that trichloroethanol, the major metabolite of trichloroethylene, induced nephrotoxicity in rats as a result of formic acid excretion and acidosis.

Toxicokinetic modelling of methyl formate exposure and implications for biological monitoring.

A toxicokinetic (TK) model was developed to describe the inhalation exposure in humans to methyl formate (MF), a catalyst used in foundries, and to discuss biological monitoring. The TK model consisted of four compartments: MF, the metabolites--methanol (MeOH) and formic acid (FA)--and, in addition, a urinary compartment describing the saturable reabsorption of FA. Levels of MeOH and FA in urine, from an experimental study (100 ppm MF, 8 h at rest), validated the present model. The TK model describes well the general behaviour of MeOH and FA in urine after MF exposure. A nonlinear and a linear relationship respectively, was predicted between MF exposure and FA or MeOH excretion in urine, and this has previously been seen after occupational MF exposure. The present model has been modified to simulate MeOH exposure as well. Generally low exposures (concentration or exercise) produce only marginal increases in FA urinary excretions, but when exposure is elevated, urinary FA excretion increases because of saturation in the mechanism of reabsorption. Using FA urinary excretion as the critical indicator, because of its link to health effects, an occupational exposure limit value for MF of no greater than 50 ppm should be selected (based on predictions with the TK model). MeOH in urine can be considered as a biomarker for MF at low exposure, because of lower background values and of a linear relationship with exposure. At higher exposures, however, FA could be used as a biomarker as it becomes progressively more sensitive. But the use of biological monitoring for MF is difficult because of individual variations in background values. Under the present state of knowledge both FA and MeOH should be used to estimate only group exposures, rather than individual exposures.

Urinary methanol and formic acid as indicators of occupational exposure to methyl formate.

To evaluate the validity of methanol (MeOH) and formic acid (FA) in urine as biological indicators of methyl formate (MF) exposure in experimental and field situations. The subjects were 28 foundrymen and two groups of volunteers (20 control and 20 exposed). Exposure assessment of the workers was performed by personal air and biological monitoring. Methyl formate vapour collected on charcoal tube was analysed by gas chromatography. The concentration of MF in the exposure chamber (volunteer-study) was monitored by two independent methods [flame ionisation detection (FID) and Fourier transformation infra-red detection (FTIR)]. Urinary metabolites (MeOH and FA) were analysed separately by headspace gas chromatography. The volunteers exposed to 100 ppm MF vapour at rest for 8 h excreted 3.62 +/- 1.13 mg MeOH/l (mean +/- SD) at the end of the exposure. This was statistically different (P < 0.001) from pre-exposure MeOH excretion (2.15 +/- 0.80 mg/1), or from that of controls (1.69 +/- 0.48 mg/l). The urinary FA excretion was 32.2 +/- 11.3 mg/g creatinine after the exposure, which was statistically different (P < 0.001) from pre-exposure excretion (18.0 +/- 9.3 mg/g creatinine) or that of controls (13.8 +/- 7.9 mg/g creatinine). In foundrymen, the urinary FA excretion after the 8 h workshift exposure to a time weighted average (TWA) concentration of 2 to 156 ppm MF showed a dose-dependent increase best modelled by a polynomial function. The highest urinary FA concentration was 129 mg/g creatinine. The pre-shift urinary FA of the foundrymen (18.3 +/- 5.6 mg/g creatinine) did not differ from that of controls (13.8 +/- 7.9 mg/g creatinine). The urinary MeOH excretion of the foundrymen after the shift, varied from < 1 to 15.4 mg/l, while the correlation with the preceding MF exposure was poor. The foundrymen excreted more (P = 0.01) FA (2.12 +/- 3.56 mg/g creatinine) after the workshift than experimentally, once-exposed volunteers (0.32 +/- 0.11 mg/g creatinine) at a similar inhaled MF level of 1 ppm). In spite of its high background level in non-exposed subjects, urinary FA seems to be a useful biomarker of methyl formate exposure. The question remains as to what is the reason for the differences in chronic and acute exposure respectively.

Trichloroethylene induced vitamin B 12 and folate deficiency leads to increased formic acid excretion in the rat

Exposure of rats to trichloroethylene induces a sustained excretion of large amounts of formic acid in urine. Both of the major metabolites, trichloroethanol and trichloroacetic acid, were found to induce this response, but not the minor metabolite S-(1,2-dichlorovinyl) cysteine. Other polychlorinated solvents, including carbon tetrachloride and chloroform, also increased urinary formate excretion. Addition of folic acid either to diet or drinking water modulated the response indicating that these rats were folate deficient. Two markers of vitamin B 12 deficiency, methylmalonic acid and 5-methyltetrahydrofolate, were also markedly increased in urine and plasma respectively. The increase in 5-methyltetrahydrofolate is consistent with a folate deficiency caused by an inhibition of the vitamin B 12 dependant methionine salvage pathway. Since both vitamin B 12 and chemicals containing polychlorinated carbon atoms readily form free radicals, it is suggested that trichloroacetic acid and trichloroethanol interact with vitamin B 12 through a free radical mechanism inducing a B 12 deficiency and, as a consequence, a folate deficiency. As a result of the folate deficiency, excess formic acid, which is normally utilised through this pathway, is excreted in urine.

P4E103 - Formic acid excretion in rats dosed with trichloroethylene: A possible explanation for long term kidney damage

P4E103 - Formic acid excretion in rats dosed with trichloroethylene: A possible explanation for long term kidney damage

Formic acid excretion in rats exposed to trichloroethylene: a possible explanation for renal toxicity in long-term studies

Rats exposed to trichloroethylene, either by gavage or by inhalation, excreted large amounts of formic acid in urine which was accompanied by a change in urinary pH, increased excretion of ammonia, and slight increases in the excretion of calcium. Following a single 6-h exposure to 500 ppm trichloroethylene, the excretion of formic acid was comparable to that seen after a 500 mg/kg dose of formic acid itself, yet the half-life was markedly different. Formate excretion in trichloroethylene treated rats reached a maximum on day 2 and had a half-life of 4–5 days, whereas urinary excretion was complete within 24 h following a single dose of formic acid itself. Formic acid was shown not to be a metabolite of trichloroethylene. When rats were exposed to 250 or 500 ppm trichloroethylene, 6 h/day, for 28 days, the only significant effects were increased formic acid and ammonia excretion, and a change in urinary pH. There was no evidence of morphological liver or kidney damage. Long-term exposure to formic acid is known to cause kidney damage suggesting that excretion of this acid may contribute to the kidney damage seen in the long-term studies with trichloroethylene.

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

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

Formate in Serum and Urine after Controlled Methanol Exposure at the Threshold Limit Value

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

Formic acid excretion in comparison with methanol excretion in urine of workers occupationally exposed to methanol.

A semiautomated head-space gas chromatographic (GC) method was developed for measuring formic acid in urine. The method consists of heating 1 ml urine sample in a 20-ml air-tight vial in the presence of 1 ml sulfuric acid and 2 ml ethanol at 60 degrees C for 30 min for ethyl esterification and air-liquid equilibrium, followed by automatic injection of 1 ml head-space air into a flame ionization detector GC. The detection limit was 1 mg/l for formic acid. The method was applied to measure formic acid in the shift-end urine samples from 88 workers exposed to methanol at 66.6 ppm (as geometric mean) and in urine samples from 149 nonexposed controls. Methanol concentrations were also determined. Regression analysis showed that urinary formic acid concentrations, as observed or corrected for either creatinine concentration or specific gravity of urine (1.016), correlated significantly with time-weighted average intensities of exposure to methanol vapor. Men excreted significantly more formic acid than women. Comparison with methanol excretion suggested, however, that urinary formic acid is less sensitive than urinary methanol as an indicator of methanol vapor exposure, primarily because the background level for formic acid (26 mg/l as arithmetic mean, or 23 mg/l as geometric mean) is more than ten times higher than the level for methanol (1.9 mg/l as arithmetic mean, or 1.7 mg/l as geometric mean). After theoretical methanol exposure at infinite concentration, the urinary formic acid/methanol ratio should be about 0.4.

Aging, chronic administration of ethanol, and acute exposure to nitrous oxide: Effects on vitamin B 12 and folate status in rats

Elderly patients with alcoholism often require surgery and receive nitrous oxide (N 2O) as a component of their anesthetic. Since aging, ethanol, and N 2O may all perturb folate and/or vitamin B 12 metabolism, we examined the combined influence of these parameters on vitamin B 12/folate status in a rodent model. Aged male Fischer 344 rats (24 months old) were given a liquid ethanol diet (35% of calories as ethanol) and control rats were pair-fed a liquid diet with carbohydrate substituting for the caloric content of ethanol. After receiving liquid diets for 7 weeks, rats were exposed to 60% N 2O/40% O 2 for 6 h. Urinary excretion of formic acid, formiminoglutamic acid (FIGLU), and methylmalonic acid (MMA) were used as indirect markers of folate/vitamin B 12 status. In both the aged ethanol-fed and control groups, excretion of formic acid and FIGLU markedly increased the first day after N 2O exposure and returned towards background values by the second day. No changes occurred in MMA excretion. Exposure to N 2O decreased methionine synthase activities in liver, kidney and brain, and recovery of methionine synthase activities occurred over a period of 4 days in both the aged ethanol-fed and control groups. Ethanol treatment for 7 weeks combined with acute exposure to N 2O did not deplete the aged rats of folate or vitamin B 12 in blood, liver, kidney or brain. Thus, in this animal model, aging, chronic ethanol administration, and acute N 2O exposure did not act synergistically to produce prolonged and severe disturbances in folate and vitamin B 12 metabolism.

Vitamin B12 and Folate Status in Rats after Chronic Administration of Ethanol and Acute Exposure to Nitrous Oxide

The chronic administration of ethanol or brief exposure to nitrous oxide (N2O) decreases the activity of hepatic methionine synthase and disrupts normal metabolic processes that require folate and vitamin B12. This combination of drugs has clinical relevance since alcoholic patients often require surgery and receive N2O as a component of their anesthetic. To assess this clinical problem using a rodent model, rats were given a liquid ethanol diet (35% of calories as ethanol) and control rats were pair-fed a liquid diet with carbohydrate substituting for the caloric content of ethanol. After receiving liquid diets for 6 weeks, rats were exposed to 60% N2O/40% O2 for 6 hr. Urinary excretions of formic acid and formiminoglutamic acid (FIGLU) were used as indirect markers of folate status. In both the ethanol-fed and control groups, excretion of formic acid and FIGLU markedly increased the first day after N2O and returned towards background values by the second day after N2O exposure. Ethanol treatment alone decreased methionine synthase activities in liver, but not kidney or brain. Exposure to N2O further decreased methionine synthase activities, and recovery of methionine synthase activity after N2O occurred over a period of 4 days at the same rate in both the ethanol-fed and control groups. Ethanol treatment for 6 weeks combined with acute exposure to N2O did not deplete the rats of vitamin B12 in blood, liver, kidney, or brain. We conclude that in this animal model, chronic treatment with ethanol does not markedly exacerbate the disturbances in folate/vitamin B12 metabolism caused by brief exposure to N2O.

Effect of Nitrous Oxide on Folate and Vitamin B12 Metabolism in Patients

Exposure to nitrous oxide (N2O) markedly enhances excretion of formic acid and formiminoglutamic acid (FIGLU) in the urine of rats, suggesting a disruption in the normal pathways of folic acid metabolism secondary to an N2O-induced inactivation of methionine synthase. We tested whether surgical patients (23 having total hip replacements and 26 having resection of acoustic neuromas) exposed to isoflurane alone or combined with N2O responded similarly. We found no increase in urinary formic acid and FIGLU in patients exposed to N2O for hip replacement, but a small, transient increase in the FIGLU-to-creatinine ratio in those undergoing resection of acoustic neuromas (mean duration of anesthesia = 9.3 h). This increase peaked at the end of anesthetic exposure and returned toward control levels by the first day after anesthesia and surgery. Low preoperative levels of red blood cell folate and low-normal levels of serum vitamin B12 did not predict an increase in formic acid or FIGLU in response to N2O. Although an occasional patient may prove highly susceptible to and develop signs of severe vitamin B12 and folic acid deficiency after exposure to N2O, our findings suggest that this is a rare event.

Disruption of Folate and Vitamin B12Metabolism in Aged Rats Following Exposure to Nitrous Oxide

The ability of nitrous oxide (N2O) to disrupt folate and vitamin B12 metabolism was examined in young (2-month), middle-aged (12-month), and elderly (24-month) Fischer 344 rats. Abnormalities in folate metabolism were assessed in a noninvasive manner by measuring the urinary excretion of formic acid and formiminoglutamic acid (FIGLU), compounds that are elevated in the urine of mammals with a deficiency in folate. After a 6-h exposure to 60% N2O/40% O2, urinary formic acid excretion increased 3- to 25-fold the first day following N2O exposure and returned to background levels by the second day after exposure in all age groups. Urinary FIGLU excretion increased 100- to 300-fold in the first day following N2O exposure, with the highest FIGLU excretion rates found in the elderly rats and the lowest in the young rats. By the second day after N2O exposure, FIGLU excretion rates returned to baseline levels in all age groups. Plasma folate progressively decreased with increasing age, whereas no age-dependent changes were observed in red cell folate, liver folate, or plasma vitamin B12 levels. The elderly rats demonstrated the highest vitamin B12 content in the liver and the lowest vitamin B12 content in the kidney compared to the other age groups. Hepatic methionine synthase activities (measured 16-21 days after N2O exposure) were elevated in the elderly compared to the middle-aged or young rats, but methionine synthase activities in kidney and brain were not different among the three different age groups. It was concluded that in rats, aging per se only slightly influences the disruption of folate metabolism produced by exposure to N2O.

Enzymatic assay of formic acid and gas chromatography of methanol for urinary biological monitoring of exposure to methanol

An enzymatic assay method for the determination of urinary formic acid is described. Formic acid in urine was cleaved to carbon dioxide and water by formic acid dehydrogenase, whereby NAD+ was converted to NADH, which reacted with INT (p-iodonitrotetrazolium violet) in the presence of NAD-diaphorase. The color thus produced was determined at 500 nm. In addition, a simple gas chromatographic method of urinary formic acid is described, in which head space gas of formic acid methylester was applied into the wide bore column. The urinary formic acid concentrations by the enzymatic method agreed well with that by the gas chromatographic method. A simple gas chromatographic method for urinary methanol assay is also described. Acetonitrile was added to an equal volume of urine containing methanol. After centrifugation, the supernatant was injected into gas chromatography (GC). The peaks of urinary methanol and ethanol were separated by GC. Formic acid and methanol in urine of unexposed healthy subjects and workers exposed to methanol were analyzed by the colorimetric and gas chromatographic methods. Geometric mean concentrations of urinary formic acid and methanol in the healthy subjects were 7.82 mg/g creatinine and 1.34 mg/l, respectively. The concentration ratio of formic acid to methanol in the urine of the workers exposed to methanol was calculated to be 3.67 +/- 2.10, which agreed with the ratio under a controlled exposure experiment. A slower excretion of formic acid than that of methanol in the urine of a volunteer was also observed.

Formaldehyde exposure at various workplaces

The results of formaldehyde determinations in the air at various workplaces in the period 1980–1988 are presented. The airborne concentrations varied between < 0.01 and 10.9 mg m −3 (mean 0.7 mg m −3). For ambient air monitoring, active sampling and capillary gas chromatography are reliable and sensitive methods. Formic acid excretion in urine is an unspecific and insensitive biological indicator for monitoring low-dose formaldehyde exposure.

Effect of renal formic acid excretion on urinary calcium and ammonia concentrations.

Intragastrically given formic acid (300 mg/kg) caused high urinary formate concentrations in rabbits with continuously decreasing urinary pH up to 30 h after the dose despite the fact that the bulk of the formate in urine was excreted within 15 h. Urinary formic acid inversely correlated to urinary ammonia in 23 workers occupationally exposed to methanol or formic acid so that the delayed urinary acidification could have been caused by the effects of formate on renal ammonia genesis. The urinary excretion of calcium was linearly correlated to the formic acid excretion by the same subjects. The latter effect may have been caused by interferences with the tubular reabsorption mechanisms for the calcium ion.