Metabolic interactions

Metabolic interactions involving ethanol can be divided into two groups: Interference with ethanol metabolism

Ethanol is metabolised via liver ADH to acetaldehyde and then via aldehyde dehydrogenase (ALDH) to acetate. Interference with aldehyde dehydrogenase by various factors can lead to an accumulation of acetaldehyde which leads to tachycardia, hypertension and hyperventilation. In the workplace, agents such as amides (e.g., dimethylformamide), oximes, thiurams, carbamates and others, have proven to be effective inhibitors of aldehyde dehydrogenase (Hills and Venable, 1982).

Ethanol altering the metabolism of other workplace chemicals

Ethanol is an effective inducer of the enzyme systems cytochrome P450 CYP2E1 and microsomal mixed function oxidase system (Cornish et al., 1977; ATSDR, 1997). As these enzymes are involved in the metabolism of several important and commonly used industrial chemicals, induction of these pathways can lead to increased toxicity of these agents.

Recreational ethanol use may also put workers more at risk from those solvents associated with long-term neurotoxicological effects (Juntunen, 1982). Geller et al. (1979) have suggested a mechanism of 'co-solvency', which may be particularly significant for nervous system tissue, where there are barriers between the circulation and the nerve cells. Membranes with a high fat content such a myelin, preferentially take up hydrophobic molecules, whereas penetration to the cytoplasm of the nerve cell bodies is facilitated by a hydrophilic molecule. Ethanol in combination with certain workplace solvents can have a synergistic effect.

Ethanol enhances the metabolism and the toxicity of benzene in animals (Baarson et al., 1982; Nakajima et al., 1985). Increased severity of benzene induced anaemia, lymphopenia and bone marrow aplasia were observed in benzene treated mice given ethanol (Baarson et al., 1982). Both ethanol and benzene are inducers of P450 CYP2E1. The enhancement of benzene induced haematotoxicity is of particular concern for benzene exposed workers who consume ethanol, since benzene can interfere with the elimination of ethanol and co-exposure may result in CNS depression (ATSDR, 1997).

• Carbon disulphide

Carbon disulphide has been shown to inhibit the activity of the enzyme aldehyde dehydrogenase; thus concurrent exposure to carbon disulphide and ethanol can increase the blood acetaldehyde concentration. It is thought that workers exposed to carbon disulphide may experience a disulfiram-like reaction when subsequently exposed to ethanol (Rainey, 1977).

• Carbon tetrachloride

The consumption of ethanol prior to or during exposure to carbon tetrachloride vapours may increase the toxicity of carbon tetrachloride (Cornish and Adefuin, 1966, 1967; Cornish et al., 1977; Sturbelt et al., 1978). Studies in mice have shown an increased incidence of hepatotoxic effects recorded in animals receiving ethanol prior to exposure to carbon tetrachloride, compared to those exposed to carbon tetrachloride alone (Cornish et al., 1977). This additive effect may result from ethanol induced induction of P450 CYP2E1, the main enzyme involved in the metabolism of carbon tetrachloride (Cornish and Adefuin, 1967; Allis et al., 1996). Initially, there is a synergistic depression of the CNS. In some cases this is followed by pulmonary oedema, kidney and liver lesions. Sturbelt et al. (1978), extrapolating from studies on rats, concluded that the moderate amounts of ethanol commonly ingested by many individuals, may be enough to increase the hepatotoxic effects of halogenated hydrocarbons such as carbon tetrachloride. Consequently, chronic ethanol ingestion may put workers more at risk of toxicity if subsequently exposed to carbon tetrachloride. Manno et al. (1996) reported that in a group of workers exposed to a carbon tetrachloride containing fire extinguisher, signs of toxicity only developed in those with a previous history of high ethanol intake.

• Chloroform

Animal studies have shown that ethanol potentiates the liver toxicity of chloroform (Klassen et al., 1966; Klassen et al., 1967). Another study found no potentiation but this may have been because the doses of ethanol used were too small (Cornish et al., 1977).

• Dimethylformamide (DMF)

Ingestion of alcohol, even a small quantity, after exposure to DMF (by ingestion or inhalation) may cause flushing (always of the face and sometimes the neck, arms, hands and chest), nausea, dizziness and tightness of the chest (a disulfiram-like reaction). The effects may occur up to 4 days after exposure (Lyle et al., 1979) and usually resolve in about 2 hours (Chivers, 1978; Lyle et al., 1979). Flushing episodes may be associated with periorbital swelling, dysgeusia (impairment of sense of taste) and wheezing (Cox and Mustchin, 1991). In one study 19 of 102 workers (18.6%) were affected (Lyle et al., 1979).

Ethanol is a competitive inhibitor of the enzyme involved in DMF metabolism (P450 CYP2E1) and exposure to DMF after ingestion of ethanol delays the appearance of the metabolites, N-(hydroxymethyl)-N-methylformamide and N-acetyl-S-(N-methylcarbamoyl)cysteine, in the urine (Mraz et al., 1992). The mechanism of action of the disulfiram-like reaction may be the inhibition of alcohol dehydrogenase, probably by a metabolite, resulting in increased concentrations of acetaldehyde after ingestion of ethanol (Cox and Mustchin, 1991). Animal studies have shown that DMF affects both ethanol and acetaldehyde concentrations (Hanasono et al., 1977).

• Glycol ethers

As ethanol is the preferred substrate of alcohol dehydrogenase (ADH), it blocks the metabolism of glycol ethers, and the production of their toxic metabolites. As a result of this interaction, ethanol is used as an antidote in glycol ether poisoning. It is only useful in the immediate phase after exposure, as administration of ethanol is of very little benefit once the glycol ether has been metabolised.

Methanol, like ethanol, is metabolised by ADH to formaldehyde, which is further metabolised to formic acid. These metabolites are highly toxic resulting in serious CNS and ocular toxicity (Bennett et al., 1953). As ethanol is the preferred substrate of ADH, it can be used as a competitive inhibitor of methanol metabolism, allowing the methanol to be eliminated unchanged. Ethanol is widely used as the antidote of choice for methanol toxicity (Jacobsen and McMartin, 1997).

Exposure to ethanol and methyl n-butyl ketone has been shown to have an additive acute CNS depressant effect in mice. This is probably due to competition between ethanol and 2-hexanol for alcohol dehydrogenase (Sharkawi et al., 1994).

• Methylene chloride

Methylene chloride and ethanol appear to have an antagonistic effect rather than an additive or synergistic interaction following acute short-term exposures. However, animal studies have shown that following chronic exposure to both agents, ethanol appears to enhance the hepatotoxic effects of methylene chloride (Balmer et al., 1976).

Ethanol appears to inhibit microsomal oxidation of MEK. In a volunteer study, ingestion of ethanol and inhalation of MEK resulted in increased MEK concentrations in the blood, suggesting that ethanol inhibited MEK metabolism. When the ethanol was ingested before exposure to MEK the blood concentration of MEK remained high throughout the exposure. When ethanol was given after cessation of MEK exposure the same effect was seen in the elimination phase. The concentration of the metabolite 2-butanol was increased almost 10 times in the presence of ethanol. The higher blood concentration of MEK in the presence of ethanol was reflected in increased exhalation and urinary excretion of MEK. The elimination of MEK through the lungs was 8% in the presence of ethanol compared to 3% without ethanol. The elimination of MEK in the urine doubled with co-exposure to ethanol but was still less than 1% of the absorbed dose (Liira et al., 1990).

Animal studies have also demonstrated that concomitant MEK exposure slows the metabolism of ethanol (Cunningham et al., 1989), and other studies have shown that MEK increases microsomal activity (Couri et al., 1977) and inhibits alcohol dehydrogenase (Cunningham et al., 1989).

• Tetrachloroethylene

In a volunteer study, ethanol blood concentrations of 300-1,000 mg/l had no effect on tetrachloroethylene blood or breath concentrations during exposure to 100 ppm. There were no interactive effects of ethanol and tetrachloroethylene on neurobehavioural or neurophysiological tests (Hake and Stewart, 1977). However, in another study, exposure to tetrachloroethylene (25 ppm) and ethanol (doses of 0.75 and 1.5 ml 100°-proof vodka/kg body weight, to achieve blood concentrations of 400 and 800 mg/l) significantly increased blood tetrachloroethylene concentrations. In contrast, blood tetrachloroethylene concentrations were not increased at 100 ppm, as tetrachloroethylene metabolism was saturated at this dose. Performance in behavioural tests was unaffected by simultaneous exposure and it was concluded that low doses of ethanol in tetrachloroethylene exposed workers did not pose a hazard (Stewart et al., 1977). Animal studies have shown that ethanol does not potentiate the liver toxicity of tetrachloroethylene (Cornish and Adefuin, 1966; Klassen et al., 1966).

• Thiuram disulphides

A widely known interaction involving ethanol is the disulfiram reaction. It is observed in workers involved in the manufacture of chemical accelerators for the rubber vulcanisation process. Workers using tetramethyl thiuram monosulphide (disulfiram) developed flushing of the face and hands, rapid pulse, hypotension, difficulty in breathing and nausea after drinking beer (Hills and Venable, 1982). It is thought that the thiuram disulphides inhibit aldehyde dehydrogenase, allowing the accumulation of acetaldehyde.

Ethanol also affects toluene metabolism. Even a low blood ethanol concentration can decrease toluene metabolism (Baelum et al., 1993). Inhalation of toluene (80 ppm for four hours) and ingestion of ethanol (1.5 ml/kg of vodka after three hours of toluene exposure) resulted in a 42.5% increase in the blood toluene concentration. However, workers who regularly drank ethanol had lower blood toluene concentrations than those who seldom drank. This suggests that toluene may induce liver enzymes (Waldron et al., 1983). In another survey, workers with the highest exposure to toluene and ethanol had lower liver enzyme concentrations compared to controls with high ethanol but low toluene exposure (Boewer et al., 1988). The reason for this is unclear.

• Trichloroethylene

Alcohol dehydrogenase is thought to be one of the main enzymes involved in the metabolism of trichloroethylene. Concurrent exposure to ethanol appears to greatly alter the metabolism of trichloroethylene, increasing the concentration of trichloroethylene, and its metabolites chloral hydrate and trichloroethanol. There may also be an increase in ethanol and acetaldehyde concentrations (Hills and Venable, 1982; Koppel et al., 1988). Human volunteers who inhaled trichloroethylene at 50 ppm for six hours daily for five days and simultaneously ingested ethanol (blood concentration 600 mg/l) showed a 2.5-fold increase in blood trichloroethylene concentration (Müller et al., 1975). As a result of this interaction there may be an additive and increased depressive effect on the CNS and mental function.

Ingestion of ethanol before or during work (but not after work), produced increases in the blood trichloroethylene concentration and decreases in the urinary excretion rates of trichloroethylene metabolites. This effect lasted until the next day. These effects were smaller with increased exposure concentrations of trichloroethylene. Induction of trichloroethylene metabolism by consumption of ethanol the evening before work caused small changes in trichloroethylene metabolism at 50 ppm, but greater changes at 500 ppm (Sato et al., 1991).

Ethanol may also enhance the hepatotoxic effects of trichloroethylene. Studies in rats found that ethanol potentiated trichloroethylene hepatotoxicity at trichloroethylene concentrations as low as 500 ppm (Nakajima et al., 1988). In another animal study, rats receiving ethanol prior to trichloroethylene exposure had AST levels approximately 75% higher than trichloroethylene exposed animals without ethanol pre-treatment (Cornish and Adefuin, 1966).

One effect of the combination of ethanol and trichloroethylene has been termed 'degreasers flush'. Workers exposed to 200 ppm of trichloroethylene daily for three weeks reported extreme dermal flushing and red blotches on the face, neck and shoulders after consumption of as little as one-half pint of beer (Stewart et al., 1974).

The metabolism of both ethanol and xylene involves the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. In an experimental study of the metabolic interaction of ethanol and m-xylene, ingestion of a moderate dose of ethanol (800 mg/kg) before exposure to xylene (6 or 11.5 mmol/m3 (145 or 280 ppm) for 4 hours) raised the blood xylene concentration by 1.5-2-fold. The urinary concentration of methylhippuric acid decreased by about 50%, whereas the excretion of the minor metabolite 2,4-xylenol was unchanged or increased. Some individuals had a transiently raised acetaldehyde concentration and this may be the cause of their dizziness and nausea (Riihimäki et al., 1982). Another volunteer study found that ethanol is only likely to affect m-xylene kinetics at high concentrations, i.e., above the occupational exposure limit. Ingestion of ethanol (the night before) and then inhalation of m-xylene at 400 ppm for two hours, resulted in lower m-xylene concentrations in blood and alveolar air compared to 100 ppm. Urinary excretion of m -methylhippuric acid was increased at 400 ppm. This study showed that ingestion of ethanol for 2 days prior to xylene exposure was enough to alter the kinetics of xylene, but only at a high xylene concentration (Tardif et al., 1994). Ethanol exposure has also been shown to modify xylene kinetics in animal studies (Savolainen et al., 1978).

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