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This paper is a toxicological review of acetone and presents the background of acetone, its chemical/physical properties, proposed mechanisms of action, metabolism information, toxicokinetics, proposed methods of reducing toxic effects, susceptible human populations and human health effects.
Chemical and physical properties of acetone are listed in Table 1. Acetone is produced endogenously and utilized in intermediary metabolism (WHO, 1998; ATSDR, 1994). As the data in Table 1 indicate, acetone is a very volatile compound and is completely soluble within water.
Proposed Mechanisms of Action
Acetone is absorbed from the lungs, gastrointestinal tract and probably from the skin. Acetone is greatly water soluble and is effortlessly taken up by the blood and widely distributed to body tissues. Within the liver, acetone is metabolized through several intermediates, but most of them are not considered toxic. Un-metabolized acetone does not appear to accumulate in any tissue, but is excreted mainly in the expired breath. Acetone irritates mucous membranes, possibly due to its lipid solvent properties, which results in eye, nose, throat, and lung irritation upon exposure to the vapors, and skin irritation upon dermal contact. The mechanism of the narcotic effects of acetone is not known, but as a solvent, acetone may interfere with the composition of the membranes, altering their permeability to ions (Adams and Bayliss 1968). Systemically, by an unknown mechanism, acetone is moderately toxic to the liver and produces hematological effects. The renal toxicity may be due to formate, which is known to be nephrotoxic (NTP 1991) and is excreted by the kidneys (Hallier et al. 1981).
Acetone increases weight in liver and kidneys, probably through the induction of microsomal enzymes, which increases the weight of the organs on account of increased protein content. Acetone also causes reproductive issues in male rats and is fetotoxic. Although the exact mechanism for many of the effects of acetone is not known, distribution studies in mice indicate that acetone and metabolites are found in all of the target organs (Wigaeus et al. 1982). One of the major effects of acetone is that it can potentially increase the toxicity of other chemicals. Acetone enhances the formation of carboxyhemoglobin by dichloromethane by inducing cytochrome P-450IIE1, which leads to enhanced metabolism of dichloromethane to carbon monoxide (Pankow and Hoffmann 1989). In other interactions, acetone enhances the neurotoxicity of ethanol by a proposed mechanism whereby acetone inhibits the activity of alcohol dehydrogenase, a reaction responsible for 90% of the elimination of ethanol (Cunningham et al. 1989). Acetone also potentiates the neurotoxicity and reproductive toxicity of 2, 5-hexanedione (Ladefoged et al. 1989; Lam et al. 1991; Larsen et al. 1991). The exact mechanism for these interactions is not clear but appears to involve decreased body clearance of 2, 5-hexanedione by acetone (Ladefoged and Perbellini 1986).
The toxicokinetics of acetone has been studied in part because of the role that acetone plays in normal metabolism and in disease states (ATSDR, 1994 ; WHO, 1998). Under starvation conditions, high-fat and low-carbohydrate diets, or uncontrolled diabetes, fat is metabolized to form acetoacetate, which then can turn into acetone (Wieland, 1968; Argiles, 1986). Under these conditions, a high level of acetyl CoA, caused by a coupling of beta-oxidation of fatty acids, a limited supply of oxaloacetate and a lack of dietary carbohydrate, can lead to ketosis. Much of the research on acetone in humans is based on individuals in these states. Mean concentrations of acetone in "normal," non-exposed adult humans have been measured as 840 :g/L in blood, 842 :g/L in urine, and 715 ng/L in alveolar air (Wang et al., 1994). Stewart et al. (1975) reported blood acetone concentrations in male subjects (prior to exposure to acetone) ranging from 0.73 to 1.29 mg% (mg/100 ml) and in female subjects as 2.86 mg%. Acetone blood concentrations in healthy individuals are reported to range from 0.3 to 2.0 mg/100 ml (Physicians' Desk Reference, 1976). Owen et al. (1982) reported plasma acetone levels in diabetics ranging from 1.55 to 8.16 mM (9 to 47 mg %). The normal endogenous acetone turnover rate (mg/kg-day) is not known.
Overall, available data indicate that humans and rodents readily absorb acetone by inhalation, ingestion, and dermal exposure. Acetone is mostly distributed throughout the body, above all in organs with high water content. Once acetone has been absorbed, it is extensively metabolized; the prevailing metabolic pathway appears to be dose-related. At low concentrations, the primary pathway appears to be through the formation of methylglyoxal. On the other hand, as the concentration of acetone increases, the propanediol pathway becomes more predominant. Although the second pathway may be involved in gluconeogenesis, it may also be used to facilitate excretion. Acetone excretion is also dose-related. In this respect, exposure to low levels of acetone leads to small losses through expiration. Acetone appears in the urine only when exposure concentrations exceed approximately 15 ppm. The proportion of acetone lost through expiration increases at high acetone concentrations.
There is evidence of similarity between the toxicokinetic data on human subjects and rodents. In both cases, metabolism proceeds by a hepatic pathway at low concentrations and by an extrahepatic pathway followed by excretion at higher concentrations (Casazza et al., 1984; Thornalley, 1996). Both species look as if they can get rid of acetone from the body effectively (Haggard et al., 1944; Sakami, 1950; Sakami and Lafaye, 1951; Stewart et al., 1975; Reichard et al., 1979; Casazza et al., 1984; Wigaeus et al., 1981; Kosugi et al., 1986a; Wang et al., 1994).
The absorption of acetone and its distribution is governed by its physicochemical parameters and related biological factors. Acetone is miscible in water and has a high vapor pressure (Table 1) and a high blood/air partition coefficient. The low Kow indicates that acetone selectively partitions into an aqueous phase rather than a lipid phase; however, acetone is also slightly lipophilic, allowing for some diffusion into tissues. This suggests that although acetone is readily absorbed into the aqueous compartments of the body the lipid component may affect the rate of absorption into the body. Collectively, these factors allow for rapid absorption via the respiratory and gastrointestinal tracts, and broad distribution throughout the body, particularly into organs with high water content. Acetone is swiftly absorbed by way of the mouth. Haggard et al. (1944) administered acetone (50 mg/kg acetone diluted in water; final concentration and total volume not provided) to male subjects and estimated that between 65 and 93% of the acetone was metabolized while the residual material was excreted from the body over a period of 2 hours. Both the level of metabolism and excretion through the lungs and urine, and the short period of time in which these occur indicate that acetone is rapidly absorbed in humans.
Anecdotal information concerning the oral absorption of acetone in humans is provided in case studies. Studies involving the accidental ingestion of acetone indicate that acetone is readily absorbed through the gastrointestinal tract. In one case study (Herman et al., 1997) a 17- month-old girl was accidently given approximately 4.88 mL/kg of acetone through her gastronomy tube and was found gagging, nonresponsive, and diaphoretic with dilated sluggish pupils. Clinical chemistry analyses demonstrated elevated levels of serum ketones. A second case study (Ramu et al., 1978) involved the accidental ingestion of nail polish remover. The subject became listless and lethargic with a shortened attention span. While both studies indirectly demonstrate that acetone is readily absorbed via the gastrointestinal tract a quantitative assessment of absorption cannot be determined.
Acetone has been broadly studied as a metabolic intermediate that is naturally formed in humans and rodents under normal metabolic conditions and at higher concentrations under conditions of fasting, ingestion of high-fat, low-carbohydrate diets, and uncontrolled diabetes. The proposed metabolic pathways for acetone are shown in Figure 1.
Based on human and animal studies and in vitro studies, the metabolism of acetone may occur via at least two routes (Figure 1). The principal metabolic pathways are dependent on the site of metabolism and on the concentration of acetone. The metabolites are incorporated into glucose and other substrates of intermediary metabolism that ultimately produce CO2. In the first metabolic step, common to all potential pathways, acetone is oxidized to acetol by acetone mono-oxygenase, an activity associated with CYP2E1. This step requires O2 and NADPH (Casazza, JP; Felver, ME; Veech, RL. (1984)). In the first pathway, acetol is converted to methylglyoxal, which in turn is metabolized to glucose through a lactate intermediate. The conversion of acetone via the methylglyoxal pathway is mediated by acetone mono-oxygenase (CYP2E1) and acetol mono-oxygenase (CYP2E1) to form methylglyoxal. The conversion of methylglyoxal to lactate is mediated by glyoxylase I and II and glutathione-S-transferase. This pathway is primarily a hepatic pathway. In the second pathway, the acetol intermediate is converted to L-1,2-propanediol by an extrahepatic mechanism that has not been fully characterized. The metabolism of acetone via the 1,2-propanediol pathway to lactate is mediated by alcohol dehydrogenase and aldehyde dehydrogenase (Dietz, DD; Leininger, JR; Rauckman, EJ; et al. (1991)). Gluconeogenesis may proceed through the formation of an active form of acetate. 1,2-Propanediol may be converted to glucose through a series of intermediates including lactate.
The data also demonstrates that the pathways for acetone metabolism are concentration-dependant. At lower concentrations, acetone is metabolized in the liver through the methylglyoxal pathway similar to biological conditions of fasting or exertion where the acetone is formed from fatty acids to produce glucose. Thus, at low plasma concentrations acetone serves as a gluconeogenic substrate. At higher concentrations an alternate pathway predominates and mediates the conversion of acetone to 1,2-propanediol. Although some studies indicate that 1,2-propanediol serves as an intermediate in the production of glucose, it is conceivable that the conversion from acetone to the diol diverts acetone from gluconeogenesis and facilitates the loss of acetone via urine. Enzymes involved in the metabolism of acetone are inducible. The metabolism of acetone through the methylglyoxal route is mediated largely by CYP2E1, which can be induced by fasting, experimental diabetes, or exposure to ethanol or acetone; therefore, acetone induces its own metabolism (ATSDR, 1994 ; Mandl et al., 1995; WHO, 1998). Inhibition of CYP2E1 activity resulted in an increase in endogenous acetone levels in rats (Chen et al., 1994). Acetone significantly increased both the microsomal protein content and the activity of CYP2E1 in rat liver 18 hours after a single oral dose of 15 mmol/kg body weight (Brady et al., 1989) and in mouse liver 24 hours after a single oral dose or administration of 1% in the drinking water for eight days (Forkert et al., 1994). Treatment with acetone or starvation conditions leads to increases in protein content and enzyme activity in the rat kidney (Ronis et al., 1998). Acetone inhalation exposure has also been shown to potentiate enzyme induction by the solvents toluene and xylene (Nedelcheva, 1996).
Susceptible Human Populations and Human Health Effects
Acetone is used industrially as a solvent and feedstock; biologically it serves a role in human metabolism during fasting/starvation. Commercial acetone is used in the production of high-volume chemicals including methacrylates, bisphenol A and other ketones, and as a solvent. Small amounts of acetone are used within the pharmaceutical industry. In humans, acetone is formed endogenously under conditions of starvation, uncontrolled diabetes, or with high fat/low carbohydrate diets. Under conditions where glucose stores are depleted acetone provides a means of supplying glucose to tissues that are incapable of metabolizing fatty acids.
Exogenous acetone is readily absorbed via inhalation, ingestion, and dermal exposures. The water solubility of acetone allows for broad distribution to the water compartments of the body. At relatively low levels of exposure acetone may be lost through expired air and metabolized through the methylglyoxal pathway. At higher levels a second pathway producing 1,2-propanediol becomes more active and non-metabolized acetone is lost through the urine. Earlier work on acetone metabolism proposed a metabolic pathway that produced an "active" form of acetate and formate. Although the active form of acetate may be acetyl CoA, the evidence to support the production of formate from acetone is sparse.
No human studies following oral exposure to acetone are available. Studies on rodent exposure to orally-administered acetone have identified several treatment-related health effects. Sub-chronic oral exposure resulted in kidney, testis, and hematologic system effects; however, the effects were characterized as mild. Although the nephrotoxic effects noted in rodents have been identified as the most critical effects, they tend to occur in male rats only and at high levels of exposure (20,000 and 50,000 ppm in drinking water).
Inhalation studies in humans have been conducted on both volunteers and occupationally-exposed individuals (Dick et al., 1988, 1989; Kiesswetter et al., 1994; Stewart et al., 1975). These studies have examined, almost exclusively, either the toxicokinetics or neurological effects of acetone. The effects reported in these studies appear to be mild and transient. Clinical studies and case reports suggest slight neurological effects, mostly of the subjective type, in individuals exposed to varying concentrations of acetone. In most studies the subjects report discomfort, irritation of the eyes and respiratory passages, mood swings, and nausea following exposure to acetone vapor at concentrations of 500 ppm or higher. The fact that the effects subside following termination of exposure indicates that acetone may be the active compound, rather than a metabolite. Clinical chemistry analyses conducted in several studies demonstrated no exposure-related effects. Data on nerve conductivity are inconclusive. Case reports of accidental poisoning also indicate that the effects (e.g., lethargy and drowsiness) are short-lived.
Proposed Methods of Reducing Toxic Effects
This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to acetone. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to acetone. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice.
Since acetone is irritating to mucous membranes of the respiratory system and eyes, people exposed occupationally wear protective clothing, goggles, and respirators (Stutz and Janusz 1988). If exposure has occurred and symptoms of narcosis are present, the victim is removed from the contaminated area, clothing is removed and isolated, the skin is washed with soapy water, oxygen is administered, and eyes are thoroughly flushed with water. In the case of ingestion of acetone, activated charcoal is given. Although induction of emesis by administration of syrup of ipecac is sometimes recommended in the case of ketones in general (Stutz and Janusz 1988), this may be contraindicated in the case of acetone ingestion because of the possibility of pulmonary aspiration, which increases for substances with high volatility and low viscosity (Goldfrank et al. 1990). Gastric lavage has been used to treat a patient who ingested acetone (Sakata et al. 1989), but the possibility of aspiration also exists for this method (Goldfrank et al. 1990).
Following inhalation or oral exposure, acetone is eliminated within about l-3 days in humans (DiVincenzo et al. 1973; Matsushita et al. 1969a, 1969b; Ramu et al. 1978; Sakata et al. 1989). Acetone does not accumulate in any tissue and its metabolites do not appear to be toxic or retained (Wigaeus et al. 1982). To reduce the body burden of acetone, a cathartic, such as magnesium sulfate in water, is administered (Stutz and Janusz 1988). In a case of isopropyl alcohol poisoning (acetone is a major metabolite of isopropyl alcohol), hemodialysis has been used successfully to enhance elimination of both isopropyl alcohol and acetone (Rosansky 1982).
Acetone itself appears to be a toxic agent, and increasing the metabolism of acetone would appear to be the best method for interfering with the mechanism of action. However, acetone induces its own metabolism by inducing cytochrome P-450IIEl (Johansson et al. 1986; Puccini et al. 1990). The first and second steps of the metabolism of acetone are dependent on cytochrome P-45OIIEl (Casazza et al. 1984; Johansson et al. 1986; Koop and Casazza 1985; Puccini et al. 1990). Since ethanol also induces this particular form of P-450IIEl (Johansson et al. 1988; Puccini et al. 1990), the metabolism of acetone might be increased by administering ethanol, although this may competitively slow acetone metabolism, at first, and induce cytochrome P-450IIEl only after a lag of several hours. However, since acetone increases the toxicity of other chemicals by inducing cytochrome P-45OIIE1, which enhances the metabolism of the chemicals to reactive intermediates, further increasing the cytochrome P-450IIEl levels might be counterproductive in cases of exposure to acetone followed by exposure to the other chemicals.
Figure 1. Pathway for the metabolism of acetone. Table 1. Chemical and Physical Properties (IRIS, 2003)
2-propanone; dimethyl ketone
CAS registry no.
Vapor pressure at 20Â°C Hg
Solubility in water
Henry's law constant
4.26 Ã- 10-5 atm-m3/mol
Conversion factors in air
1 ppm = 2.374 mg/m3
Odor threshold in air (absolute)