3.1.1. Absorption

Studies of inhalation exposures in humans indicate that, due to its high blood-air partition coefficient (167-330), acetone is rapidly and passively taken up by the respiratory tract and absorbed into the bloodstream (Fiserova-Bergerova and Diaz 1986; Haggard et al. 1944; Paterson and Mackay 1989; Sato and Nakajima 1979). Experiments in humans exposed to 23-4,607 ppm for up to 4 hours have measured pulmonary uptakes ranging from ≈30 to 80% (DiVincenzo et al. 1973; Landahl and Herrmann 1950; Nomiyama and Nomiyama 1974a; Pezzagno et al. 1986; Wigaeus et al. 1981). The reason for the wide range in reported values involves the unique aqueous wash-in/wash-out effect when acetone is inhaled, which can lead to spurious results (Schrikker et al. 1985, 1989). During this phenomenon, acetone, which is highly water soluble, will dissolve in epithelial cells during inspiration (wash-in) and evaporate during expiration (wash-out). This could account for the lower than expected pulmonary absorption based on the high blood/air partition coefficient (Johanson 1991; Wigaeus et al. 1981). Exhaled breath levels of acetone in humans rose during exposure and reached steady-state within ≈2 hours during exposure to concentrations between 125 and 250 ppm (Brown et al. 1987; Nomiyama and Nomiyama 1974a).

Uptake and absorption of acetone in humans following inhalation exposures depends on factors such as concentration, duration, and level of physical activity. Uptake was directly proportional to exposure concentration and duration (DiVincenzo et al. 1973; Wigaeus et al. 1981). Uptake also increased as the level of physical activity increased, due to increased pulmonary ventilation (DiVincenzo et al. 1973; Haggard et al. 1944; Jakubowski and Wieczorek 1988; Wigaeus et al. 1981). Lungs (including the mouth and trachea) retained a greater percentage of inspired acetone (55%) than the nasal cavity (18%) in humans, indicating that the nasal cavity absorbs acetone less readily than the rest of the respiratory system (Landahl and Herrmann 1950). Blood levels of acetone rose rapidly during exposure for up to 4 hours with no indication that steady-state was reached (Brown et al. 1987; Dick et al. 1989; DiVincenzo et al. 1973), suggesting that during exposure, the rate of absorption exceeded the rate of distribution and elimination. In humans exposed to 100 or 500 ppm acetone for 2 or 4 hours, 75-80% of the amount of acetone inspired was absorbed by blood after 15 minutes of exposure, and 20-25% remained in the dead space volume (DiVincenzo et al. 1973). Higher inspired amounts resulted in higher blood levels (DiVincenzo et al. 1973; Haggard et al. 1944; Matsushita et al. 1969a; Pezzagno et al. 1986). A correlation between blood level at the end of exposure and exposure concentration was found in humans exposed to 23-208 ppm for 2-4 hours (Pezzagno et al. 1986). No significant difference in uptake or retention was found between men and women (Brown et al. 1987). External temperature appears to alter absorption of inhaled acetone. An experimental study in five human subjects showed that for a constant air concentration of acetone (495 ppm), blood levels of acetone increased as the external temperature increased from 21 to 30°C (Marchand et al. 2021). After a 4-hour exposure at 21°C, the mean venous blood acetone concentration was 22.14 mg/L, compared to 27.65 ppm at 30°C, an increase of approximately 25%. The study authors suggested that the increased venous blood concentrations at higher temperatures was due to physiological changes associated with thermoregulation.

Studies on absorption of acetone following oral exposure in humans are limited but likewise indicate high levels of absorption, as with inhalation exposure. In a series of experiments conducted in male volunteers given acetone orally at 40-80 mg/kg, an estimated 65-93% of the administered dose was eliminated via metabolism, with the remainder excreted in the urine and expired air in about 2 hours, indicating rapid and extensive gastrointestinal absorption (Haggard et al. 1944). In a human who ingested 137 mg/kg acetone on an empty stomach, the blood level of acetone rose sharply to a peak 10 minutes after dosing (Widmark 1919). In other experiments, the subject ingested the same dose 10 or 12 minutes after eating porridge. The blood acetone level rose slowly over 48-59 minutes to levels of about one-half to two-thirds of that achieved after taking acetone on an empty stomach. Thus, the presence of food in the gastrointestinal tract may lead to a slower rate of absorption.

Measurement of acetone in blood and urine of patients who accidentally or intentionally ingested acetone indicated that acetone was absorbed, but the percentage absorbed cannot be determined from the data. In one case, a man ingested liquid cement that provided an approximate dose of acetone of 231 mg/kg (Sakata et al. 1989). His plasma acetone level was about 110 μg/mL and his urinary level was 123 μg/mL 5 hours after ingestion, but he had been subjected to gastric lavage. In another case, a woman who had ingested nail polish remover had a blood acetone level of 0.25 g/100 mL (2.5 mg/mL) upon admission to the hospital (Ramu et al. 1978). The authors estimated that her body burden was 150 g acetone at the time of admission. The serum acetone level of a 30-month-old child was 445 mg/100 mL (4.45 mg/mL) 1 hour after ingestion of a 6-ounce bottle of nail polish remover (65% acetone) (Gamis and Wasserman 1988).

Dermal absorption of acetone has also been demonstrated in humans. Application of cotton soaked in acetone to a 12.5 cm² uncovered area of skin of volunteers for 2 hours/day for 4 days resulted in blood levels of acetone of 5-12 μg/mL, alveolar air levels of 5-12 ppm, and urinary concentrations of 8-14 μg/mL on each day (Fukabori et al. 1979). Higher blood, alveolar air, and urinary levels were obtained when the daily exposure increased to 4 hour/day: 26-44 μg/mL in blood, 25-34 ppm in alveolar air, and 29-41 μg/mL in urine. The absorption was fairly rapid, with peak blood levels appearing at the end of each daily application. Although precautions were taken to limit inhalation of acetone vapors, the study authors noted that it was not possible to completely prevent inhalation, and the acetone concentration in the breathing zone of one subject was found to be 0.4-0.6 ppm. From the alveolar air and urine concentrations, it was estimated that a 2-hour dermal exposure over 12.5 cm² of skin was equivalent to a 2-hour inhalation exposure to 50-150 ppm, and a 4-hour dermal exposure was equivalent to a 2-hour inhalation exposure to 250-500 ppm acetone.

Similar to humans, animals also absorb acetone rapidly during inhalation exposure. Measurement of blood acetone levels in 13-week-old male and female rats after 4-6 hours of exposure to various concentrations shows that blood levels correlate well with exposure concentrations (Charbonneau et al. 1986a, 1991; NTP 1988) and are highest immediately after exposure (NTP 1988). In male rats exposed to 1.50 ppm for 0.5-4 hours, measurement of blood acetone concentrations during exposure revealed that blood levels increased steadily for 2 hours and then remained constant for the next 2 hours of exposure (Geller et al. 1979b). Blood acetone levels also correlated well with exposure concentration in dogs exposed for 2 hours (DiVincenzo et al. 1973). Blood levels were 4, 12, and 25 mg/L after exposures to 100, 500, and 1,000 ppm, respectively. Comparison of uptakes in dogs and humans revealed that humans

absorbed a greater absolute quantity under comparable exposure conditions, but when expressed in terms of kg body weight, male and female dogs absorbed 5 times more than humans. In anesthetized dogs allowed to inhale concentrated vapors of acetone spontaneously from a respirator at various ventilation rates, uptake by the respiratory tract was 52% at flow rates of 5-18 L/minute and 42% at ventilation rates of 21-44 L/minute (Egle 1973). Retention in the lower respiratory tract was 48% at 4-18 L/minute and 37.5% at 21-50 L/minute. Retention by the upper respiratory tract was 57% at 4-18 L/minute. The effect of exposure concentration on total uptake was studied at a range of ventilation rates equated with exposure concentrations. Percent uptakes were 52.1% at a mean concentration of 212 ppm, 52.9% at 283 ppm, and 58.7% at 654 ppm. These results indicate the respiratory uptake of acetone by dogs is similar to human uptake values reported by Landahl and Herrmann (1950). The retention in the upper respiratory tract was higher than in the lower respiratory tract of dogs (Egle 1973). Exposure concentration had little effect on retention. The absorption of acetone by the nasal walls of anesthetized dogs, in which the nasal passage was isolated, increased when the airflow rate was increased (Aharonson et al. 1974). This suggests that increased airflow decreases the proportion of acetone that reaches the lungs.

In rats exposed continuously to 2,210 ppm for 9 days, peak acetone blood levels of approximately 1,020-1,050 mg/L were reached in 3-4 days and remained at this level for the duration of exposure (Haggard et al. 1944). In rats exposed to 4,294 ppm for 12 days, acetone blood levels plateaued at 2,420-2,500 mg/L in 4 days. Blood levels in rats exposed to these concentrations for 8 hours/day were about half of those reached during continuous exposure. The amount of acetone absorbed in the first 8 hours exceeded the amount eliminated in the next 16 hours of exposure to fresh air, leading to a small accumulation. However, the accumulation during intermittent exposure did not reach the levels achieved during continuous exposure. In other experiments of rats exposed to 2,105-126,291 ppm, the time to peak blood level decreased as the exposure concentration increased (Haggard et al. 1944).

As was found in humans (Landahl and Herrmann 1950) and dogs (Egle 1973), disposition of acetone in the upper respiratory tract of rats, mice, guinea pigs, and hamsters indicates that relatively little acetone is absorbed from the upper respiratory tract (Morris 1991; Morris and Cavanagh 1986, 1987; Morris et al. 1986, 1991). The deposition efficiency was greater in Sprague-Dawley rats than in Fischer-344 rats. Deposition was similar in B6C3Fl mice and Fischer-344 rats, and greater than in Hartley guinea pigs and Syrian golden hamster. No difference was found between male and female Sprague-Dawley rats (Morris et al. 1991). The differences among strains and species could not be attributed to differences in metabolism because acetone is not significantly metabolized in the upper respiratory tract of these species (Morris 1991). Rather, the difference was attributed to differences in upper respiratory tract perfusion rates (Morris 1991; Morris and Cavanagh 1987).

Experiments in rats indicated that acetone is rapidly and almost completely absorbed from the gastrointestinal tract after oral exposure. No studies were located regarding absorption of acetone in other animal species after oral exposure to acetone. A rat given ¹⁴C-acetone at a dose of 1.16 mg/kg expired 47.4% of the dose as ¹⁴C-carbon dioxide over the 13.5-hour collection period (Price and Rittenberg 1950). Another rat given about 7.11 mg/kg ¹⁴C-acetone by gavage once a day for 7 days expired 67-76% of the administered radioactivity as ¹⁴C-carbon dioxide and 7% as ¹⁴C-acetone over a 24-hour period after the last dose. From these data, absorption of least 74-83% of the administered dose can be inferred. A rat dosed with 6.19 mg/kg ¹⁴C-acetone expired 4.24% of the radiolabel as unchanged ¹⁴C-acetone over 5.5 hours, indicating rapid absorption. In rats given a single gavage dose of 1,177 mg/kg acetone, the maximum blood level of 850 μg/mL was reached in 1 hour and declined gradually to about 10 μg/mL over 30 hours (Plaa et al. 1982). In another experiment, peak blood levels and the time to peak blood levels were compared after various gavage doses to rats. After a dose of 78.44 mg/kg, the maximum blood level of acetone of about 200 μg/mL was reached in 3 hours and declined to 10 μg/mL at 12 hours, where it remained for the next 12 hours. After a dose of 196.1 mg/kg, the peak blood level was 400 μg/mL at 6 hours and declined biphasically to 50 μg/mL at 12 hours and to 30 μg/mL at 18 hours where it remained for the next 6 hours. After a dose of 784.4 mg/kg, the peak level was 900 μg/mL at 1 hour and declined to 300 μg/mL at 12 hours, 110 μg/mL at 18 hours, and 50 μg/mL at 24 hours. After a dose of 1,961 mg/kg, the peak level was 1,900 μg/mL at 3 hours and declined slowly to 400 μg/mL at 24 hours. In other studies where rats were given similar or higher doses of acetone, plasma acetone levels rose proportionately with dose in rats given acetone as single doses by gavage (Charbonneau et al. 1986a; Lewis et al. 1984) or in the drinking water for 7 days (Skutches et al. 1990).

In a study comparing blood levels of acetone in fasting male rats to those in male rats that received oral doses of acetone, peak blood levels of acetone of about 35 and 110 μg /mL were reached within about 3 hours after dosing of rats with 78 and 196 mg/kg acetone, respectively (Miller and Yang 1984). The levels returned to background levels within the next 16 hours. At an acetone dose of 20 mg/kg, the blood level increased to about 5 μg/mL over 19 hours, when the rats were sacrificed. In rats fasted for 48 hours, blood acetone levels increased continuously to about 13 μg/mL. While the maximal blood concentrations of the treated rats differed considerably from that of the fasting group, the areas under the curve for the 78 and 196 mg/kg groups were comparable to the fasting groups.

Conflicting data were located regarding the effect of vehicle on the gastrointestinal absorption of acetone. In one study, maximum blood levels were higher and achieved earlier in male rats given acetone by gavage in water than in rats given acetone by gavage in corn oil (Charbonneau et al. 1986a). The slower absorption of acetone in corn oil may have resulted from a delayed gastric emptying due to the presence of corn oil (fat) in the stomach. In a later study, however, very little difference in blood and liver levels of acetone were found in male rats given the same dose of acetone in water or in corn oil (Charbonneau et al. 1991).

There are little data regarding the absorption of acetone in animals after dermal exposure. One study reported a permeability coefficient (K_p) for acetone of 0.00249 cm-hour⁻¹ when administered to the skin of newly deceased piglets (Schenk et al. 2018). The findings of cataract formation in guinea pigs exposed dermally (Rengstorff and Khafagy 1985; Rengstorff et al. 1972) (see Section 2.12) indicated that acetone was absorbed from the skin of the guinea pigs.

3.1.2. Distribution

There are limited data regarding distribution of acetone or its metabolites in humans. Biomonitoring conducted in workers at a plastics factory found similar regression slopes between air concentrations or acetone and its levels in serum, whole blood, and urine, indicating that acetone is evenly distributed throughout the body (Mizunuma et al. 1993). Acetone was detected in cerebrospinal fluid in a 55-year-old man who ingested 1 L of acetone (Gregoire et al. 2018). In addition, acetone is well absorbed into the blood from the respiratory and gastrointestinal tract of humans (see Section 3.1.1) and is highly water soluble. Therefore, widespread distribution, especially to tissues with high water content, is expected.

Biomonitoring studies in humans indicate that maternal-fetal transfer and maternal-infant transfer of acetone occur. Acetone was identified in maternal and cord blood collected at the time of delivery, indicating transplacental transfer (Dowty et al. 1976). Of eight samples of breast milk from lactating women from four urban areas, all were found to contain acetone (Pellizzari et al. 1982). Whether the source of acetone was endogenous or exogenous could not be determined. Nevertheless, the data indicate that acetone is distributed to mother’s milk, and represents a source of excretion from the mother and exposure for infants.

The distribution of acetone has been studied in mice exposed to acetone by inhalation (Wigaeus et al. 1982). Mice were exposed to 500 ppm ¹⁴C-acetone for 1, 3, 6, 12, and 24 hours or for 6 hours/day for 1, 3, or 5 consecutive days, after which they were immediately killed. Radioactive unmetabolized acetone and total radioactivity were found in blood, pancreas, spleen, thymus, heart, testes, vas deferens, lungs, kidneys, brain, liver, muscle, brown adipose tissue, subcutaneous adipose tissue, and intraperitoneal adipose tissue. A common feature was an increase in tissue concentration of acetone and total radioactivity during the first 6 hours after exposure, with no further accumulation observed after 6 hours except in the liver and brown adipose tissue. The continued accumulation of radioactivity in these tissues could be the result of high metabolic turnover. Only about 10% of the radioactivity in the liver at 24 hours was unmetabolized acetone. When the mice were exposed intermittently on 3 or 5 consecutive days, most tissues showed no or only a small additional increase in radioactivity after more than 1 day of exposure; however, the concentration in adipose tissue increased significantly with increasing exposure duration up to 5 days. Elimination of acetone was fastest in blood, kidneys, lungs, brain, and muscles with half-lives of about 2-3 hours during the first 6 hours after exposure. The slowest elimination was in subcutaneous adipose tissue with a half-time of >5 hours. Elimination of acetone was complete in all tissues by 24 hours after exposure, but total radioactivity, indicative of metabolites, was still present in all tissues except blood and muscle. These data indicate that acetone is not selectively distributed to any tissues but is more evenly distributed in body water. In addition, acetone is not likely to accumulate with repeated exposure.

In another study of inhalation exposure, rats (n=4) were exposed to 1,000 ppm of acetone for 8 hours/day for 3 consecutive days (Scholl and Iba 1997). Plasma concentrations of acetone were 122, 107, and 125 μg/mL at 30 minutes after exposure on days 1, 2, and 3, respectively. Plasma elimination followed first-order kinetics in rats that were terminated after exposure to 1,000 ppm for 3 hours/day for 3 days. The half-life for elimination was 4.5 hours, and the area under the curve (AUC) was 950 μg-hour/mL. Inhalation exposure of the rats to 1,000 ppm of acetone for 3 hours/day for 10 days resulted in concentrations of 35.3 μg/g of acetone in plasma, 13.2 μg/g in liver, 11.4 μg/g in the lung, and 21.8 μg/g in the kidney (Scholl and Iba 1997).

Acetone has also been detected in the plasma of rats following oral exposures. In rats receiving acetone in drinking water (7.5% v/v) for 11 consecutive days, plasma concentrations of acetone on day 1 were in the range of 315-800 μg/mL. The plasma concentration appeared to plateau at about 1,200 μg/mL by day 4 (Scholl and Iba 1997). Acetone was additionally found in the liver of rats after oral exposure (Charbonneau et al. 1986a, 1991). No other studies were located regarding the distribution of acetone or its metabolites in animals. However, acetone is well absorbed from the gastrointestinal tract (see Section 3.1.1) and is highly water soluble. Therefore, widespread distribution, especially to tissues with high water content, is expected.

No studies were located regarding distribution of acetone or its metabolites in animals after dermal exposure. However, the findings of cataract formation in guinea pigs exposed dermally (Rengstorff and Khafagy 1985; Rengstorff et al. 1972) (see Section 2.12) indicated that acetone was absorbed from the skin of the guinea pigs and distributed to the eyes.

Similar to humans, there is evidence of transplacental transfer of acetone in animals. Acetone and its metabolites were found in fetuses from rats injected intravenously with 100 mg/kg acetone on GD 19 (Peinado et al. 1986).

One study investigated the pharmacokinetics of intravenously injected radiolabeled acetone in baboons (Gerasimov et al. 2005). Acetone uptake in the brain was rapid in both the cerebellum and white matter, reaching peaks of approximately 0.02% of the injected dose within 1-2 minutes after injection. Acetone had a half-time of clearance from peak uptake of 31 and 38 minutes in the cerebellum and white matter, respectively. The brain/blood uptake ratio for acetone reached a peak of 1.0 and plateaued around 4-5 minutes after injection.

3.1.3. Metabolism

The metabolic fate of acetone is independent of route of administration and involves three separate gluconeogenic pathways, with ultimate incorporation of carbon atoms into glucose and other products and substrates of intermediary metabolism with generation of carbon dioxide. The metabolic pathways appear to be similar in humans and animals. The primary (major) pathway involves hepatic metabolism of acetone to acetol and hepatic metabolism of acetol to methylglyoxal, while two secondary (minor) pathways are partially extrahepatic, involving the extrahepatic reduction of acetol to L-1,2-propanediol. Some of exogenous acetone is unmetabolized and is excreted primarily in the expired air with little acetone excreted in urine (see Section 3.1.4).

The only studies located regarding the metabolism of acetone in humans were conducted in non-obese fasted, obese fasted, and male and female diabetic patients (Reichard et al. 1979, 1986). The involvement of gluconeogenesis was demonstrated in non-obese patients fasted for 3 days (n=6), obese patients fasted for 3 days (n=6), and obese patients fasted for 21 days (n=3) before intravenous injection of 2-[¹⁴C]-acetone (Reichard et al. 1979). The percentages of ¹⁴C-glucose in plasma derived from ¹⁴C-acetone were 4.2, 3.1, and 11.0% in the three respective groups, suggesting the involvement of gluconeogenesis. Cumulative ¹⁴C-carbon dioxide excretion by the lungs during the 6-hour collection period accounted for 17.4, 21.5, and 4.9% in the three respective groups. Radioactivity was also incorporated into plasma lipids and plasma proteins. Unmetabolized acetone in the expired air accounted for 14.7, 5.3, and 25.2%; urinary excretion of acetone accounted for 1.4, 0.6, and 1.3%, respectively; and in vivo metabolism accounted for 83.9, 94.1, and 73.5%, respectively, of the radioactivity. Intravenous infusion of 2-[¹⁴C]-acetone into patients with diabetic ketoacidosis resulted in a mean plasma acetone turnover rate of 6.45 μmol/kg/minute (Reichard et al. 1986). Analysis of glucose in urine revealed a labeling pattern in five of the six patients consistent with the involvement of pyruvate in the gluconeogenic pathway. A different pathway may have operated in the other patient. Acetol and 1,2-propanediol were also detected in the plasma, and the concentrations of these metabolites were directly related to the plasma level of acetone. The results demonstrated high plasma acetone levels in decompensated diabetic patients. The suggested pathway of acetone metabolism in these patients was acetone to acetol to 1,2-propanediol to pyruvate and ultimately to glucose, but other pathways may exist between subclasses of diabetic patients.

The metabolism of acetone has been studied extensively in animals, primarily in rats, and three separate pathways of gluconeogenesis have been elucidated (Figure 3-1). These pathways are consistent with the metabolic fate of acetone in humans, discussed above. The elucidation of these pathways has been performed in experiments in which rats, mice, or rabbits were exposed by inhalation, by gavage, via drinking water, or by intravenous, subcutaneous, or intraperitoneal injection of nonradiolabeled acetone or to acetone labeled with 14C in the methyl groups, number 2 carbon atom, or all three carbon atoms (Casazza et al. 1984; Hallier et al. 1981; Hetenyi and Ferrarotto 1985; Johansson et al. 1986; Koop and Casazza 1985; Kosugi et al. 1986a, 1986b; Mourkides et al. 1959; Price and Rittenberg 1950; Puccini et al. 1990; Rudney 1954; Sakami 1950; Sakami and LaFaye 1951; Skutches et al. 1990). In these experiments, identification of metabolites in liver, plasma, or urine, the labeling patterns of ¹⁴C incorporation into metabolites from ¹⁴C-acetone in plasma or in liver, or the results of enzyme reactions using microsomes from acetone treated animals have led to the pathways illustrated in Figure 3-1.

Figure 3-1

Proposed Metabolic Pathway for Acetone in Humans.

In the first step, acetone is oxidized (hydroxylation of a methyl group) to acetol by acetone monooxygenase (also called acetone hydroxylase), an activity that is associated with CYP2E1 and requires oxygen and NADPH (Casazza et al. 1984; Johansson et al. 1986; Koop and Casazza 1985; Puccini et al. 1990). CYP2E1 can be induced by fasting, experimental diabetes, or exposure to ethanol or acetone (Johansson et al. 1988; Patten et al. 1986; Puccini et al. 1990). When the rate of acetone oxidation was evaluated in microsomes with acetone added to the incubation system, microsomes from rats (Johansson et al. 1986) and mice (Puccini et al. 1990) pretreated with acetone had a 7-8 times greater acetone oxidation rate than microsomes from control rats or mice. Thus, acetone induces its own metabolism.

The formation of acetol is common to all three pathways. Subsequent conversion of acetol to methylglyoxal in microsomes is catalyzed by acetol monooxygenase (also called acetol hydroxylase), an activity that is also associated with CYP2E1 and requires oxygen and NADPH (Casazza et al. 1984; Johansson et al. 1986; Koop and Casazza 1985). Methylglyoxal can then be converted to D-glucose by an unidentified pathway, and/or possibly by catalysis by glyoxalase I and II and glutathione to D-lactate, which is converted to D-glucose (Casazza et al. 1984). The conversion of methylglyoxal to D-lactate by the actions of glyoxalase I and II is well established (Racker 1951), but may represent a minor pathway in the metabolism of acetone (Casazza et al. 1984; Kosugi et al. 1986a, 1986b; Thornalley 1990). The unidentified pathway by which methylglyoxal is converted to D-glucose may involve conversion of methylglyoxal to pyruvate by 2-oxoaldehyde dehydrogenase, an activity identified using aqueous extracts of sheep liver acetone powders (Monder 1967).

Investigations that included CYP2E1-null mice have confirmed the importance of CYP2E1 in acetone catabolism in vivo (Bondoc et al. 1999; Chen et al. 1994). In the study of Bondoc et al. (1999), acetone levels were measured in non-fasted and 48-hour-fasted wild type and CYP2E1-null mice. Fasting is known to result in the elevation of acetone levels in the blood. Blood acetone levels in non-fasted wild type and CYP2E1-null mice were not significantly different from one another. However, fasted CYP2E1-null mice exhibited 24-fold increased blood acetone levels compared to their non-fasted controls. The wild-type fasted mice, on the other hand, exhibited only a 2- to 4-fold increase in blood acetone levels compared to their non-fasted controls. Chen et al. (1994) assessed the role of CYP2E1 in acetone catabolism by measuring acetone levels at different time points in rats that had been treated with diallyl sulfide (DAS, a CYP2E1 inhibitor) at a variety of dose levels. The study authors noted DAS dose-dependent increases in the time to peak blood acetone level and in the time to return to pre-dose levels, suggesting an important role of CYP2E1 in acetone catabolism.

In the second and third pathways, acetol is converted to L-1,2-propanediol by an extrahepatic mechanism that has not been characterized (Casazza et al. 1984; Kosugi et al. 1986a, 1986b; Rudney 1954; Skutches et al. 1990). The two pathways then diverge from the point of production of 1,2-propanediol. In the second pathway, 1,2-propanediol formed extra-hepatically returns to the liver where it is converted to L-lactaldehyde via nicotinamide adenine dinucleotide (NADH)-dependent alcohol dehydrogenase (Casazza et al. 1984; Kosugi et al. 1986a, 1986b), and L-lactaldehyde, in turn, is converted to L-lactate (Casazza et al. 1984; Ruddick 1972; Rudney 1954) via NADH-dependent aldehyde dehydrogenase (Casazza et al. 1984). L-lactate can then be converted to D-glucose (Casazza et al. 1984). In the third pathway, the L-1,2-propanediol formed extra-hepatically returns to the liver where it is degraded by an uncharacterized mechanism to acetate and formate (Casazza et al. 1984; Ruddick 1972).

Several studies have traced the labeling patterns of ¹⁴C from 2-[¹⁴C]-acetone or 1,3-[¹⁴C]-acetone to gluconeogenic precursors and formate to incorporation of ¹⁴C into glycogen, glycogenic amino acids, fatty acids, heme, cholesterol, choline, and urea (Mourkides et al. 1959; Price and Rittenberg 1950; Sakami 1950). The pattern of labeling suggested the involvement of the “acetate and formate” pathway. The ultimate fate of glucose is entry into glycolysis or into the tricarboxylic acid cycle, via pyruvate and acetyl coenzyme A (CoA) with the liberation of carbon dioxide, and subsequent electron transport and oxidative phosphorylation with the production of ATP (Lehninger 1970). Fatty acids, amino acids, and glycogen may also enter stages of intermediary metabolism.

The relative importance of the three pathways in the metabolism of acetone may depend upon the amount of acetone administered. When a trace amount of 2-[¹⁴C]-acetone was administered intravenously to rats, the pattern of incorporation of ¹⁴C into glucose was consistent with the production of glucose via the methylglyoxal/lactate pathway (Kosugi et al. 1986a). When a higher dose of 2-[¹⁴C]-acetone (325 mg/kg) was injected, the pattern of incorporation was more consistent with the 1,2-propanediol pathway. These results suggest that at low doses of acetone or endogenous acetone, the methylglyoxal and lactate pathways predominate, but at higher doses, these pathways become saturated and metabolism is shunted to the formate-acetate branch of the 1,2-propanediol pathway.

In addition to the pathways illustrated in Figure 3-1, 2,3-butanediol (Casazza et al. 1984) and isopropyl alcohol (Lewis et al. 1984) were detected in the blood of rats after oral dosing with acetone and were deemed to be unrelated to the ingestion of these chemicals. The positions of 2,3-butanediol and isopropyl alcohol in the metabolic scheme are not clear.

That acetone is extensively metabolized has been demonstrated by the finding of high percentages of ¹⁴C-carbon dioxide in the expired air of animals exposed to ¹⁴C-acetone (Mourkides et al. 1959; Price and Rittenberg 1950; Sakami 1950; Sakami and LaFaye 1951; Wigaeus et al. 1982) (see Section 3.1.4).

Although the liver is the primary site of acetone metabolism, radioactive unmetabolized acetone and total radioactivity were found in blood, pancreas, spleen, thymus, heart, testes, vas deferens, lungs, kidneys, brain, liver, muscle, brown adipose tissue, subcutaneous adipose tissue, and intraperitoneal adipose tissue of mice after inhalation exposure to ¹⁴C-acetone (Wigaeus et al. 1982) (see Section 3.1.2). The fraction of total radioactivity that was not still acetone represented metabolites. Elimination of acetone was complete in all tissues by 24 hours after exposure, but total radioactivity, indicative of metabolites, was still present in all tissues except blood and muscle. Whether these tissues (other than the liver) were capable of metabolizing acetone or whether the metabolites themselves were distributed to the tissues was not clear. However, microsomes from the lungs of hamsters exposed to acetone in drinking water for 7 days had a 500% increased activity of aniline hydroxylase, an enzyme associated with CYP2E1 (Ueng et al. 1991). Furthermore, the level of CYP2E1 increased 6-fold in microsomes from the nasal mucosa of rabbits exposed to acetone in drinking water for 1 week (Ding and Coon 1990). In hamsters given drinking water containing acetone for 7 days (Ueng et al. 1991) or 10 days (Menicagli et al. 1990), microsomes prepared from kidneys had increased levels of CYP and cytochrome b. These results suggest that acetone metabolism, which involves CYP2E1, may occur in the lungs and kidneys of hamsters and the nasal mucosa of rabbits. Incubation of acetone with homogenates of nasal mucosa from mice indicated that acetone was metabolized via a NADPH-dependent pathway in vitro, but no evidence of in vivo metabolism of acetone by the upper respiratory tract was found in mice, rats, guinea pigs, or hamsters (Morris 1991). Injection of pregnant rats with acetone on GD 19 resulted in high levels of 1,2-propanediol and acetol in the fetuses (Peinado et al. 1986). Whether these findings reflect transfer of the metabolites from the dams or metabolism of transferred acetone by the fetuses was not resolved.

Very few differences have been found among species in the metabolism of acetone. The pathways illustrated in Figure 3-1 appear to operate in rats, mice, and rabbits. In microsomes from rabbits exposed to acetone via drinking water, it was found that the oxidation of acetol could be catalyzed by cytochromes P-4503b (IIC3), 2 (IIB6), and 4(IA2), as well as by cytochrome P-4503a (P-450IIE1) (Koop and Casazza 1985). Only CYP2E1 could catalyze the oxidation of acetone to acetol. No studies were located regarding the ability of other isoenzymes of CYP to catalyze these reactions in other species.

Physiological or genetic status may alter the metabolism of acetone. When nondiabetic and diabetic 6-week-old male rats were treated by gavage with 99.5% pure acetone (containing <0.01% isopropyl alcohol) at doses of 1,000, 2,000, or 4,000 mg/kg, isopropyl alcohol deemed unrelated to the ingestion of the chemical was detected in the blood (Lewis et al. 1984). The levels of isopropyl alcohol and acetone increased with increasing dose in the diabetic rats, although with plateaus for both acetone and isopropyl alcohol at 1,000 and 2,000 mg/kg doses, but leveled off in the nondiabetic rats, indicating either saturation of the metabolic pathway from acetone to isopropyl alcohol or a reversibility of the conversion at high doses. It was suggested that in the diabetic rats, acetone and NADH, both needed for isopropyl alcohol production from acetone, presumably via alcohol dehydrogenase, may be diverted to gluconeogenic pathways to meet the diabetic rat’s need for glucose, resulting in the short plateau. The subsequent rise of both compounds at the high dose of acetone in the diabetic rats could be accounted for by greater generation of NADH from fatty acid oxidation in the diabetic rat, which reduces acetone to isopropyl alcohol, accounting for the rising level of isopropyl alcohol. Liver homogenates from mice heterozygous for the obesity gene treated with acetone were more effective in converting acetone to lactate than liver homogenates from non-obese homozygous mice treated with acetone (Coleman 1980). The more effective conversion by heterozygous mice may account for their prolonged survival on the starvation regimen, compared with non-obese mice. In pregnant and virgin rats (either fed or fasted) injected intravenously with acetone, plasma acetol levels were not significantly different between fasted and nonfasted rats, but pregnant rats had significantly lower levels than virgin rats (Peinado et al. 1986). Liver levels of acetol were also significantly lower in pregnant rats than in nonpregnant rats. Methylglyoxal levels were very high in the livers and plasma of nonfasted rats (pregnant or nonpregnant), but fasting resulted in much lower levels. No major differences were found in the expiration of carbon dioxide between fasted and diabetic rats injected intraperitoneally with acetone (Mourkides et al. 1959) or in the labeling pattern of ¹⁴C derived from ¹⁴C-acetone into glucose among nonfasted diabetic, fasted diabetic, nondiabetic nonfasted, and fasted nondiabetic rats injected intravenously with ¹⁴C-acetone (Kosugi et al. 1986a, 1986b).

3.1.4. Excretion

The main route of excretion of acetone is via the lungs, regardless of the route of exposure. Acetone is excreted both unchanged and, following metabolism, mainly as carbon dioxide. Studies have been conducted in humans exposed by inhalation, but these studies have followed the elimination only of unchanged acetone from blood and the excretion of unchanged acetone in the expired air and urine.

A case report of a 55-year-old man who ingested 1 L of acetone estimated a terminal half-life of 17 hours (Gregoire et al. 2018). In humans exposed to acetone up to 1,250 ppm for up to 7.5 hours/day in a complex protocol for 16 weeks, the concentration of acetone in venous blood was directly related to the vapor concentration and duration of exposure, and inversely related to the time elapsed following exposure (Stewart et al. 1975). The rate of elimination of acetone from blood was constant regardless of blood acetone concentration (DiVincenzo et al. 1973). Half-times for blood elimination of 3-3.9 hours have been estimated in humans exposed to 100-500 ppm for 2-4 hours (Brown et al. 1987; DiVincenzo et al. 1973; Wigaeus et al. 1981). A study of workers exposed to 0.34 ppm during an 8-hour shift found an estimated half-life of 5.8 hours for acetone in blood (Wang et al. 1994). Elimination half-times of 3.9 and 6.2 hours have been estimated for arterial and venous blood, respectively, in volunteers (n=8) exposed to acetone concentrations ranging from 712 to 1,309 ppm (Wigaeus et al. 1981). No differences in elimination half-times were found between men and women (Brown et al. 1987). The elimination from blood was found to be complete in 24 hours after a 6-hour exposure in subjects exposed to 250 ppm, in 32 hours in subjects exposed to 500 ppm, and in 48 hours in subjects exposed to 1,000 ppm (Matsushita et al. 1969a). When 22 year-old men were exposed to 250 ppm for 6 hours/day for 6 days, the blood levels of acetone rose each day and returned to baseline levels in the morning after each daily exposure (Matsushita et al. 1969b). At an exposure concentration of 500 ppm, however, the blood levels declined each day, but not to baseline levels. At the end of the 6-day exposure, blood acetone levels declined to baseline within 2 days for the 250 ppm group and within 3 days for the 500 ppm group. Another study measured urinary acetone on the morning after occupational exposure to acetone concentrations above 300 ppm and found elevated concentrations relative to baseline (Satoh et al. 1995). However, by the end of the second day of exposure, there was no evidence of significant acetone accumulation; urinary acetone concentrations were similar to those at the end of the first day. From the half-time and the data on time to return to baseline levels, it appears that at higher concentrations, acetone may accumulate slightly in the blood during daily intermittent exposure, such as would be experienced by workers.

The rate and pattern of respiratory excretion of acetone is influenced by exposure concentration, duration, the level of physical activity during exposure, and biological sex. In humans exposed to acetone up to 1,250 ppm for up to 7.5 hours/day in a complex protocol for up to 6 weeks, the rate of respiratory excretion was a function of the duration, and the concentration of acetone in breath after exposure was directly related to the time-average concentration during exposure, with constant duration (Stewart et al. 1975). The length of time after exposure in which acetone could be detected in the expired air was related to the magnitude of exposure, with acetone still readily detectable 16 hours after exposure to 1,000 or 1,250 ppm for 7.5 hours. Excretion of acetone by the lungs was complete within 20 hours postexposure in humans exposed to 237 ppm for 4 hours (Dick et al. 1989). During exposure for 2 hours, the acetone concentration in expired air rose to 20 ppm in humans exposed to 100 ppm and to 90-100 ppm in those exposed to 500 ppm (DiVincenzo et al. 1973). After exposure to 100 ppm, the expired air concentration of acetone declined biphasically over the next 7 hours to 5 ppm. However, after exposure to 500 ppm, the expired air concentration dropped sharply to 2 ppm and declined to 1 ppm over the next 7 hours. DiVincenzo et al. (1973) observed prolonging the exposure duration to 4 hours resulted in a <2-fold increase in acetone levels in postexposure expired air, which may reflect a greater loss of acetone through metabolism and urinary excretion. Exercise during the exposure period increased the elimination almost 2-fold. In humans exposed to acetone at rest, during exercise at a constant workload, or during exercise with step-wise increments in workload, expiration of acetone via the lungs amounted to 63, 74, and 138 mg, respectively, at approximately 0.25-4 hours postexposure and to 48, 77, and 197 mg, respectively, over the next 4-20 hours (Wigaeus et al. 1981). Excretion of acetone from the lungs and kidneys (combined) amounted to 16, 20, and 27% of the amount absorbed in the three respective groups of subjects. Urinary excretion amounted to only 1% of the total uptake. Women expired acetone more slowly than men after a 4-hour exposure to 127-131 ppm, but the percentages excreted by the lungs were not statistically significantly different between men and women (17.6% for men, 15.0% for women) (Nomiyama and Nomiyama 1974b).

Very little unchanged acetone is excreted in the urine (DiVincenzo et al. 1973; Kawai et al. 1992; Vangala et al. 1991; Wigaeus et al. 1981). Urinary excretion is biphasic (Pezzagno et al. 1986). Peak urinary excretion occurred between 1 and 3.5 hours after exposure (Matsushita et al. 1969b; Wigaeus et al. 1981). In male volunteers exposed to 497 or 990 ppm acetone for 4 hours, cumulative acetone excretion in urine at 18 hours after cessation of exposure was 89.5 mg, suggesting slow excretion of acetone in the urine (Vangala et al. 1991). The amount of acetone excreted in the urine is influenced by the exposure concentration, duration of exposure, and level of physical activity during exposure. The acetone concentration in the urine ranged from 0 to 17.5 mg/L at the end of the 8-hour workshift in 45 workers exposed to 0-70 ppm acetone (baseline urinary concentration in 343 nonexposed subjects averaged 1.5 mg/L) (Kawai et al. 1992). Acetone levels in the preshift urine samples were significantly higher than baseline levels when acetone exposure on the previous day was >15 ppm. There was no significant difference between baseline urine levels and preshift urine levels when the previous day’s exposure was <15 ppm. In humans exposed for 6 hours, peak urinary levels were found within the first hour after exposure and were 5.2 mg/dL in subjects exposed to 1,000 ppm, 2.9 mg/dL in subjects exposed to 500 ppm, and 1.8 mg/dL in subjects exposed to 250 ppm (Matsushita et al. 1969b). The returned to baseline levels occurred within 48 hours for the 1,000 ppm group, within 32 hours for the 500 ppm group, and within 24 hours in the 250 ppm group. When human subjects were exposed for 6 hours/day for 6 days, urinary levels of acetone rose each day and declined to baseline levels by the following morning each day when the exposure concentration was 250 ppm (Matsushita et al. 1969a). At an exposure level of 500 ppm, however, urinary levels declined each day, but not to baseline levels. At the end of the 6-day exposure period, urinary acetone levels returned to baseline within 2 days for the 250 ppm group and within 3 days for the 500 ppm group. Therefore, excretion was more complete after exposure to lower concentrations, and at higher concentrations, acetone may accumulate somewhat during daily intermittent exposure, such as would be experienced occupationally. Total 24-hour urine content of acetone was 1.25 mg in subjects exposed to 100 ppm for 2 hours and 3.51 mg in subjects exposed to 500 ppm for 2 hours (DiVincenzo et al. 1973). Prolonging the duration to 4 hours in the 100-ppm group resulted in a total of 1.99 mg acetone in the urine. A slight increase in the urinary content of acetone (1.39 mg) was found when humans exposed to 100 ppm for 2 hours exercised during the exposure. The nature of physical activity during exposure also influenced the urinary excretion. At 3-3.5 hours after exposure, 8.5, 8.5, and 13.4 mg were excreted by the kidneys in subjects exposed at rest, during exercise at a constant workload, and during exercise with stepwise increments in workload, respectively (Wigaeus et al. 1981).

One human controlled exposure study on excretion was identified, in which volunteers ingested 60-80 mg/kg acetone (Haggard et al. 1944). The elimination of acetone in expired air and urine was determined; acetone concentration in expired air was measured 1 hour after administration and 30 minutes thereafter and in urine, acetone concentrations were determined 2 hours later. Over an observation period of 4 hours, the authors estimated that 64-93% of the administered dose was metabolized and 7-36% was eliminated via urine and expired air.

The only other information regarding excretion of acetone in humans after oral exposure is from case reports of accidental or intentional ingestion of materials containing acetone plus other components that may have influenced the elimination of acetone. In a man who ingested liquid cement containing 18% acetone (231 mg/kg), 28% 2-butanone, and 29% cyclohexanone and 720 mL sake (alcoholic beverage), the plasma level of acetone was ≈1,120 μg/mL 5 hours after ingestion and declined to 65 μg/mL at 18 hours, 60 μg/mL at 24 hours, and <5 μg/mL at 48 hours (Sakata et al. 1989). A first-order plasma elimination rate constant of 0.038/hour and a half-time of 18.2 hours were calculated. The urinary level of acetone decreased gradually from about 123 μg/mL at 5 hours after ingestion to about 61 μg/mL at 19 hours. In a case of an individual known to have alcohol use disorder who had ingested nail polish remover and whose blood acetone level was 0.25 g/dL (2.5 mg/mL) upon admission to the hospital, the blood level of acetone declined in a log-linear manner to about 0.06 g/dL (0.6 mg/mL) about 86 hours after admission, with a half-life of 31 hours (Ramu et al. 1978). The calculated clearance of acetone from the lungs was 29 mL/minute or 0.39 mL/minute/kg. A half-time of 25 hours for lung clearance was calculated, which is in agreement with the observed plasma elimination half-time of 31 hours. The serum acetone level of a 30-month-old male child was 445 mg/100 mL (4.45 mg/mL) 1 hour after ingestion of a 6-ounce bottle of nail polish remover (65% acetone) and declined to 2.65 mg/mL at 117 hours, to 0.42 mg/mL at 48 hours, and to 0.04 mg/mL at 72 hours (Gamis and Wasserman 1988). The half-time of acetone in this patient was 19 hours in the severe early stage and 13 hours in later stages of intoxication, which suggested to the authors greater metabolism and/or excretion in children, compared with adults. Information regarding excretion of acetone after dermal exposure of humans is limited, but the main route of excretion is via the lungs, with little excreted in the urine. Application of an unspecified quantity of acetone to a 12.5 cm² area of skin of volunteers for 2 hours/day for 4 days resulted alveolar air levels of 5-12 ppm and urinary concentrations of 8-14 μg/mL on each day (Fukabori et al. 1979). These levels returned to baseline levels by the next day after each exposure. Higher alveolar air and urinary levels were obtained when the daily exposure increased to 4 hours/day: 25-34 ppm in alveolar air, and 29-41 μg/mL in urine, but these levels also returned to baseline each day.

Physiological status may influence the disposition of endogenous and exogenous acetone in humans. In groups of nonobese patients fasted for 3 days, obese patients fasted for 3 days, and obese patients fasted for 21 days and injected intravenously with ¹⁴C-acetone, 8-29% of the urinary acetone was ¹⁴C-labeled (Reichard et al. 1979). The concentrations of urinary acetone were 1.2, 0.4, and 2.6 μmol/mL in 3-day-fasted nonobese, 3-day-fasted obese, and 21-day-fasted obese patients, respectively. The rates of urinary acetone excretion were 1.2, 0.4, and 1.7 μmol/minute, respectively, suggesting marked renal reabsorption or back-diffusion. The percentages of measured acetone production that could be accounted for by excretion via the lungs were 14.7, 5.3, and 25.2%, respectively. The percentages that could be accounted for by urinary excretion were 1.4, 0.6, and 1.3%, respectively. Cumulative excretion of ¹⁴C-carbon dioxide during the 6-hour turnover study periods accounted for 17.4, 21.5, and 4.9%, respectively. Thus, nonobese subjects fasted for 3 days excreted more acetone at higher rates than did obese subjects fasted for 3 days. However, excretion by the obese patients fasted for 21 days exceeded that by both 3-day-fasted groups. These differences are probably related to the effect that the degree of starvation ketosis has on the metabolism and overall disposition of acetone.

As in humans, acetone is excreted mainly by the lungs of animals. Studies in animals have followed the elimination of acetone from blood and tissues, excretion of acetone and carbon dioxide in expired air, and the urinary excretion of formic acid.

Blood levels of acetone were highest immediately after a 4-hour exposure of rats to acetone (Charbonneau et al. 1986b). In rats exposed to 10,000 ppm, the blood level dropped from 2,114 to 5 μg/mL in 25 hours. In rats exposed to 15,000 ppm, the blood level dropped from 3,263 to 50 μg/mL after 25 hours. Elimination from blood was biphasic in rats exposed to 10,000 and 15,000 ppm, perhaps indicating saturation. Elimination from blood was triphasic in rats exposed to 1,000, 2,500, or 5,000 ppm and was complete within 17-25 hours. In dogs exposed to 100, 500, or 1,000 ppm acetone for 2 hours, blood levels declined in a log-linear manner with a half-time of 3 hours, similar to that observed in humans (DiVincenzo et al. 1973). Blood levels declined from 25 mg/L immediately after exposure to 10 mg/L at 5 hours postexposure for the 1,000 ppm group, from 12 to 3 mg/L for the 500 ppm group, and from 4 to 1.5 mg/L for the 100 ppm group. Elimination of radioactivity and ¹⁴C-acetone was fastest from blood, kidney, lung, brain, and muscle tissues of mice exposed to 500 ppm ¹⁴C-acetone for 6 hours, with half-times of 2-3 hours during 6 hours postexposure (Wigaeus et al. 1982). Elimination of acetone was complete in 24 hours in all tissues, but radioactivity (indicative of metabolites) was still present in all tissues except blood and muscle. When rats were exposed for 5 days, acetone tended to accumulate in adipose tissue.

Excretion of acetone in air followed pseudo-first-order kinetics in rats exposed to <20 ppm acetone for 1-7 days, while at higher concentrations, saturation kinetics were observed (Hallier et al. 1981). In male rats exposed to 500 ppm ¹⁴C-acetone for 6 hours, 42 μmol of radioactive acetone and 37 μmol ¹⁴C-carbon dioxide were excreted in the expired air during a 12-hour postexposure period, with 95 and 85%, respectively, recovered in the first 6 hours postexposure (Wigaeus et al. 1982). Radioactive acetone accounted for 52% and radioactive carbon dioxide accounted for 48% of the expired radioactivity. The concentration of acetone in the expired breath of dogs exposed to 100, 500, or 1,000 ppm acetone for 2 hours declined in a log-linear manner (DiVincenzo et al. 1973). The breath levels were directly related to the magnitude of exposure. Breath levels declined from 1.6 ppm at 30 minutes after exposure to 0.3 ppm at 300 minutes in the 100-ppm group, from 6.8 to 1.5 ppm in the 500 ppm group, and from 15 to 4 ppm in the 1,000 ppm group.

Urinary excretion of formic acid was followed for 7 days in rats exposed to 62,000 ppm acetone for 2 days. The rate of formic acid excretion was 344 μg/hour compared with 144 μg /hour in controls (Hallier et al. 1981).

Information regarding the excretion of acetone after oral exposure in animals is available only for rats. As is the case after inhalation exposure, acetone, mainly as carbon dioxide, is excreted primarily by the lungs. In a rat given 1.16 mg/kg ¹⁴C-acetone by gavage in water, expiration of ¹⁴C-carbon dioxide totaled 47.4% of the administered radioactivity over the 13.5-hour collection period (Price and Rittenberg 1950). In another experiment, a rat was given 7.11 mg/kg radioactive acetone. A small amount of radioactive acetone (10%) was found in the expired air. Radioactive carbon dioxide and acetate were also detected. In a rat made diabetic by alloxan and given 6.15 mg/kg ¹⁴C-acetone, a total of 7.29% of the administered radioactivity was expired as acetone and 51.78% as carbon dioxide. Radioactive acetate was detected in the urine. These data indicate that very little acetone (<10%) was excreted by the lungs after small doses of acetone. A major fraction was oxidized to carbon dioxide and some of the derived carbon was used for acetylation. The diabetic rat was also able to oxidize acetone, but only to ≈70% of that in the nondiabetic rat.

The dose of acetone influences the elimination of acetone from blood (Plaa et al. 1982). At a dose of 78.44 mg/kg, the maximum blood level of 200 μg/mL at 3 hours declined to 10 µg/mL at 12 hours, where it remained for the next 12 hours (data inadequate to calculate total body clearance). At a dose of 196.1 mg/kg, the maximum blood level of 400 µg/mL at 6 hours declined biphasically to 50 µg/mL at 12 hours and to 30 µg/mL at 18 hours where it remained at 24 hours (total body clearance of 64 mL/hour). At a dose of 784.4 mg/kg, the maximum blood level of 900 µg/mL at 1 hour declined to 300 µg/mL at 12 hours, to 110 µg/mL at 18 hours, and to 50 µg/mL at 24 hours (total body clearance of 86 mL/hour). At a dose of 1,961 mg/kg, the maximum blood level of 1,900 µg/mL at 3 hours declined slowly to 400 µg/mL at 24 hours (total body clearance of 75 mL/hour). Thus, total body clearance was independent of dose, but the half-time for elimination increased from 2.4 hours for 196.1 mg/kg, to 4.9 hours for 784.4 mg/kg, and 7.2 hours for 1,961 mg/kg.

The vehicle (corn oil or water) in which acetone is administered has little influence on the elimination of acetone from blood (Charbonneau et al. 1986a). After gavage treatment of rats with 78, 196, 392, 784, or 1,177 mg/kg acetone in corn oil or water, elimination was biphasic for the two higher doses and triphasic for the lower doses. Acetone elimination from blood declined to <5 to <10 µg/mL by 18-26 hours for all doses, but minor differences were found between water and corn oil as vehicle. The blood concentration curves from rats given acetone in water more closely resembled those from rats exposed by inhalation.

No studies were located regarding excretion of acetone by animals after dermal exposure.

Contrary to evidence from human studies, no major differences were observed among fed non-diabetic rats, fasted non-diabetic rats, and fed diabetic rats in the excretion of ¹⁴C-carbon dioxide from the lungs after intraperitoneal injections of ¹⁴C-acetone (Mourkides et al. 1959). However, the dose level influenced the pattern of metabolism and, hence, the excretion of carbon dioxide. Rats that received 9.3-22.7 mg/kg radioactive acetone rapidly metabolized acetone, as evidenced by exhalation of 24-43% of the administered radioactivity as ¹⁴C-carbon dioxide within the first 3 hours after dosing. Rats that received 258-460 mg/kg radioactive acetone exhaled only 2.1-5.7% of the radiolabel as carbon dioxide in the first 3 hours, 2.8-7.8% in the next 3-6 hours, and 16-29% in the next 6-24 hours. Rats injected subcutaneously with ¹⁴C-acetone also excreted the derived radioactive carbon mainly as carbon dioxide. In rats fasted for 24 hours and given 170 mg/kg radioactive acetone, 27% of the radiolabel was excreted as carbon dioxide in 4 hours (Sakami and LaFaye 1951). Rats fasted for 48 hours before the subcutaneous dose of 174 mg/kg radioactive acetone excreted 53% of the radiolabel as carbon dioxide over a 14-hour collection period (Sakami 1950).

Fasted pregnant rats had an enhanced capacity for acetone elimination compared with fasted or fed virgin rats or fed pregnant rats, after intravenous dosing with 100 mg/kg (Peinado et al. 1986). While the elimination of acetone from plasma was biphasic in all groups, the fasted pregnant rats eliminated acetone at a faster rate than the other groups.

3.1.5. Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

PBPK models use mathematical descriptions of the uptake and disposition of chemical substances to quantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that will be delivered to any given target tissue following various combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to quantitatively describe the relationship between target tissue dose and toxic endpoints.

PBPK models have been developed to simulate the behavior of acetone in rats and humans exposed by various routes (Clewell et al. 2001; Gentry et al. 2002; Huizer et al. 2012; Kumagai and Matsunaga 1995; Mörk and Johanson 2006). Clewell and coworkers (Clewell et al. 2001; Gentry et al. 2002) developed a PBPK model intended to simulate the behavior of isopropanol and its major metabolite, acetone, in rats and humans for intravenous, intraperitoneal, oral, inhalation, and dermal exposure. The model was specifically intended to be used for human health risk assessment for isopropanol. The model is capable of simulating exposures to acetone as well (Gentry et al. 2003) and was expanded to simulate exposure to isopropanol during pregnancy (Gentry et al. 2002). Validation of acetone metabolism was performed by use of intravenous, oral, and inhalation exposure data from rats and by use of inhalation and oral exposure data from humans. Huizer et al. (2012) used a similar model to investigate uncertainty and variability in biological parameters after simulated occupational exposure to isopropanol. The PBPK model developed by Mörk and Johanson (2006) accounts for variation in workload by separating working and resting muscle groups.

The PBPK model of Kumagai and Matsunaga (1995) was designed to account for uptake of acetone in the mucous layer of the respiratory tract. By adjusting the value for the volume of the mucous layer and the rate of respiration, the study authors found that the simulated acetone concentrations in arterial blood, end exhaled air, urine, and fatty tissues were well matched to experimental data.

Mörk and Johanson (2006) designed a PBPK model for acetone to account for differences in the behavior of acetone in blood and exhaled air at different levels of physical exercise. The model involves deeper parts of the mucous membrane in absorption and desorption of acetone than the ones used in previous modeling exercises and includes separate compartments for working and resting muscles. In a follow-up study, the authors used Bayesian population analysis to derive improved estimates of population variability and uncertainty in the PBPK model parameters (Mörk et al. 2009). Using the PBPK model, Mörk and Johanson (2010) derived chemical-specific adjustment factors (CSAFs) for acetone by Monte Carlo simulations. According to the simulations, CSAFs for occupational exposure were 1.6, 1.8, and 1.9 for 90^th, 95^th, and 97.5^th percentiles, respectively. The corresponding CSAFs for the general population were 2.1, 2.9, and 3.8. CSAFs for children from 3 months of age to 10 years of age were 4.2-4.8, 4.7-5.0, and 5.0-5.9 for the 90^th, 95^th, and 97.5^th percentiles, respectively.

3.1.6. Animal-to-Human Extrapolations

Acetone appears to have similar target organs in animal and humans, such as the hematological system and the CNS. Toxicokinetic studies have been conducted in both humans and animals, especially in humans exposed by inhalation. There appears to be very few differences between animal species, and the dog appears to be a good model for extrapolating absorption results to humans (DiVincenzo et al. 1973). Metabolic pathways have been elucidated primarily in rats, but mice and rabbits have also been studied. Metabolism involves three different pathways of gluconeogenesis (Casazza et al. 1984; Kosugi et al. 1986a, 1986b). The first step in the metabolism of acetone is dependent on CYP2E1 (Casazza et al. 1984), which acetone induces, and this induction has been demonstrated in rats (Johansson et al. 1988), mice (Bánhegyi et al. 1988), hamsters (Ueng et al. 1991), and rabbits (Ding and Coon 1990). It appears that the metabolic pathways operate in all tested species. The distribution of acetone has been studied only in mice exposed by inhalation (Wigaeus et al. 1982). Acetone was widely distributed to organs and tissues throughout the body. This is expected to be true for all species by virtue of its high water solubility, facilitating distribution through the water compartments of the body.

3.3.1. Biomarkers of Exposure

Acetone concentrations in expired air, blood, and urine have been monitored in a number of studies of humans exposed to acetone in the workplace as well as in controlled laboratory situations, and studies show that acetone levels in the body are an accurate indicator of acetone exposure (Leung and Paustenbach 1988). A study of 659 factory workers exposed to acetone occupationally reported a strong positive correlation between acetone levels in workplace air and acetone levels in workers’ urine after their shift (Ghittori et al. 1987). However, acetone is cleared from breath, urine, and blood within 1-3 days, so these methods are useful for monitoring only for recent exposure to acetone. In addition, these methods can be used to detect or confirm relatively high exposure to acetone, such as what might occur in the workplace or from accidental ingestion; but they cannot be used to detect lower environmental exposures in the general population at levels that are expected to be lower than those observed in occupational settings. The detection of acetone odor in the breath can alert a physician that a nondiabetic patient has been exposed to acetone (Harris and Jackson 1952; Strong 1944). It should be noted that exposure to other chemicals that are metabolized to acetone, such as isopropyl alcohol, could also lead to elevated blood, expired air, or urinary levels of acetone.

Levels of endogenous acetone can fluctuate greatly due to normal diurnal variations (Wildenhoff 1972). In addition, physical exercise (Koeslag et al. 1980), nutritional status and fasting (Jones 1987; Kundu et al. 1993; Levy et al. 1973; Lewis et al. 1977; Neiman et al. 1987; Reichard et al. 1979; Rooth and Carlstrom 1970; Williamson and Whitelaw 1978), trauma (Smith et al. 1975), and pregnancy and lactation (Bruss 1989; Paterson et al. 1967) place high energy demands upon the body, resulting in increased fatty acid utilization and higher than average blood levels of acetone. Diabetes (Kobayashi et al. 1983; Levey et al. 1964; Reichard et al. 1986; Rooth 1967; Rooth and Ostenson 1966) and alcohol use (Phillips et al. 1989; Tsukamoto et al. 1991) may result in higher levels of endogenous acetone. Infants and young children typically have higher acetone in their blood than adults due to their higher energy expenditure (Peden 1964). These factors and physiological states can complicate measuring acetone levels in blood, breath, and urine for biomonitoring purposes.

In a group of 115 workers, alveolar air samples obtained during the workshift were collected at the same time as breathing zone acetone concentrations (Brugnone et al. 1980). The mean ratio of alveolar air acetone and breathing zone acetone was 0.288. Correlations were high between alveolar air concentrations and breathing zone concentrations. Because the alveolar air samples and breathing zone concentrations were collected at the same time, and because the equilibration of alveolar air with environmental air requires some time, the alveolar samples might not necessarily reflect the environmental concentration. Similar results were obtained in a group of 20 workers in a shoe factory in which the mean environmental air concentrations ranged from 10 to 12 ppm at four sampling times (Brugnone et al. 1978). The mean alveolar concentrations ranged from 2.75 to 3.75 ppm at three sampling times during the workshift. The correlation was good between workroom air concentration and alveolar air concentration, indicating that alveolar air concentrations of acetone are useful for monitoring concurrent occupational exposure to acetone. In a group of 110 male workers exposed to acetone for an average of 14.9 years, alveolar air samples were collected before work and at the end of work on 2 consecutive days (Fujino et al. 1992). The breathing zone concentrations of acetone were measured for each individual with personal monitors and ranged from 0 to about 1,200 ppm, with most concentrations between 100 and 500 ppm. The average concentration of acetone in alveolar air before exposure on the first day was 2.95 ppm. Alveolar air concentrations at the end of the workday (range of about 20-300 ppm, average not reported) correlated strongly with exposure concentrations (r=0.65). It was estimated that the alveolar air concentrations corresponding to 750 ppm (the current American Conference of Governmental Industrial Hygienists [ACGIH] TLV for short-term exposure to acetone) and to the Japan Association of Industrial Health acceptable concentration of 200 ppm were 177 and 56.2 ppm, respectively.

Expired air concentrations of acetone have also been studied in volunteers exposed to acetone in controlled laboratory situations. In 11 men and 11 women exposed to 237 ppm acetone for 2 or 4 hours, alveolar breath samples collected immediately after exposure contained mean levels of acetone of 21.5 ppm in those exposed for 2 hours and 25.8 ppm in those exposed for 4 hours (Dick et al. 1989). The alveolar air concentrations of acetone dropped to 12.8 ppm by 90 minutes after the 4-hour exposure and to baseline levels of 0.6 ppm by 20 hours postexposure. In humans exposed to acetone at up to 1,250 ppm for up to 7.5 hours/day in a complex protocol for up to 6 weeks, the rate of respiratory excretion was a function of the duration, and the concentration of acetone in breath after exposure was directly related to the time-average concentration during exposure, with constant duration (Stewart et al. 1975). The length of time after exposure in which acetone could be detected in breath was related to the magnitude of exposure; acetone was still readily detectable 16 hours after exposure to 1,000 or 1,250 ppm for 7.5 hours. Breath analysis can be used as a rapid method to estimate the magnitude of recent acetone exposure, but should only be used to assess recent exposures because the elimination of acetone in expired air is generally complete within 1 day.

As discussed in Section 3.1.4, the level and nature of physical activity, the exposure concentration, the duration of exposure, and biological sex can influence the rate and amount of acetone elimination in the breath (DiVincenzo et al. 1973; Nomiyama and Nomiyama 1974a, 1974b; Pezzagno et al. 1986; Wigaeus et al. 1981). In general, more acetone is expired faster following exposure to high concentrations than to low concentrations (DiVincenzo et al. 1973). Doubling the duration of exposure almost doubles the total amount of acetone expired. Exercise during exposure eliminates nearly twice the amount in expired air compared with exposure to the same concentration at rest, due to increased uptake from increased pulmonary ventilation. Furthermore, exercising at stepwise increments in workload during exposure results in greater respiratory elimination than exercising at a constant workload (Wigaeus et al. 1981). Women appeared to expire acetone more slowly than men, but the total expired by women was not statistically significantly different than the total expired by men (Nomiyama and Nomiyama 1974a, 1974b).

Acetone is mainly excreted in the expired air after oral exposure as well as after inhalation exposure (see Section 3.1.4). Because urinary clearance of acetone is minimal, the calculated clearance of acetone from the lungs was 29 mL/minute or 0.39 mL/minute/kg for a patient who ingested nail polish remover using an average minute ventilation of 9.65 L/minute based on the patient’s age, weight, and sex (Ramu et al. 1978). With a volume of distribution of 0.82 L/kg, the calculated half-life was 25 hours.

Monitoring of expired air for acetone exposure should take into consideration baseline levels of acetone, because acetone is produced endogenously in the body, especially during fasting and in diabetics. In addition, the ingestion of ethanol can influence the breath levels of acetone. Endogenous levels of acetone in normal humans averaged 0.56 ppm (Phillips and Greenberg 1987). Endogenous levels of acetone in alveolar air in a group of volunteers in an experimental study averaged 0.108 ppm (Wigaeus et al. 1981). Breath sampling of volunteers under normal conditions found a mean alveolar gradient (difference between concentrations in exhaled air and inhaled ambient air) of 27.91 for acetone, indicating that the rate of in vivo synthesis is greater than the rate of clearance (Phillips et al. 1999). In healthy men who had fasted for 12 hours, the breath acetone levels ranged from 0.96 to 1.7 ppm (Jones 1987). Fasting for 36 hours resulted in average acetone breath levels of 14-66 ppm. However, in fasting men who ingested 0.25 g/kg of ethanol, the breath acetone levels decreased by 40% after a 12-hour fast and by 18% after a 36-hour fast (Jones 1988).

Acetone is metabolized to carbon dioxide (see Section 3.1.3), which is eliminated in expired air (see Section 3.1.4). However, because carbon dioxide is the main constituent of normal expired air, expired carbon dioxide has not been monitored to determine acetone exposure.

Although unchanged acetone is excreted mainly by the lungs, urinary levels are sufficiently high for monitoring purposes. In a group of 104 workers employed at factories in which breathing zone levels of acetone ranged from <242 to <1,452 ppm, urine was collected before the workshift and 4 hours after the shift started (Pezzagno et al. 1986). A close correlation was found between the TWA workroom concentration and the urinary concentration of acetone. The equation obtained was: urinary concentration (µmol/L) = 0.033 × TWA environmental concentration (µmol/m3) − 0.005 (r=0.94, n=104). In another study of 28 workers, personal breathing zone monitoring revealed wide variation depending on the type of job and ranged from <1 to 30 ppm (Kawai et al. 1990a). Results of stationary monitoring revealed workroom concentrations ranging from 1.4 to 16.2 ppm. Urine was collected at the end of the workshift, and acetone was detected in the urine of all the workers. The concentration of acetone in urine was linearly correlated with the breathing zone concentration as follows: acetone in urine (mg/L) = 0.10 + 0.40 × breathing zone concentration (ppm) (r=0.90, p<0.01). Therefore, urinary levels of acetone are useful for monitoring occupational exposure. In another study, postshift urinary levels of acetone in 45 workers exposed to 0-70 ppm acetone ranged from 0 to 17.5 mg/L (Kawai et al. 1992). The baseline urinary level of acetone in nonexposed subjects was 1.5 mg/L. Acetone levels in preshift urine samples were significantly higher than baseline levels when acetone exposure on the previous day was >15 ppm, but there was no significant difference between baseline urine levels and preshift urine levels when acetone exposure on the previous day was <15 ppm. In a group of 110 male workers exposed to acetone for an average of 14.9 years, urine samples were collected before work and at the end of work for 2 consecutive days (Fujino et al. 1992). The breathing zone concentrations of acetone were measured for each individual with personal monitors and ranged from 0 to about 1,200 ppm, with most concentrations between 100 and 500 ppm. The average urinary concentration before exposure on the first day was 2.44 mg/L. Urinary levels at the end of the workshift (range of about 5-150 ppm, average not reported) correlated with exposure concentration (r=0.71). It was estimated that the urinary concentrations corresponding to 750 ppm (the current ACGIH TLV for short-term exposure to acetone) and to the Japan Association of Industrial Health acceptable concentration of 200 ppm were 76.6 and 21.6 mg/L, respectively.

Acetone has also been detected in the urine of 15 men and women exposed to acetone under controlled laboratory conditions. In volunteers exposed to 23-208 ppm for 2-4 hours, the urinary concentrations of acetone immediately after exposure ranged from 18.8 to 155.2 µmol/L and displayed statistically significant linear relationships with the exposure concentrations (Pezzagno et al. 1986). The regression equation for subjects exposed for 2 hours at rest was: acetone in urine (µmol/L) = 0.0125 × environmental concentration (µmol/m³) + 5.87 (r=0.98, n=5). For subjects exposed for 4 hours at rest the equation was: acetone in urine (µmol/L) = environmental concentration (µmol/m³) + 6.97 (r=0.96, n=5). For the subjects exposed for 2 hours with exercise, the equation was: acetone in urine (pmol/L) = environmental concentration (µmol/m³) − 4.52 (r=0.99, n=5). At 4 hours after the cessation of exposure, the urine concentration increased to 120% of that measured immediately after exposure, then fell to 65% at 7 hours, 45% at 9 hours, 35% at 12 hours, and 15% at 20 hours post-exposure. Urinary acetone was completely cleared within 20 hours from subjects exposed to 242 or 542 ppm for 2 hours, regardless of whether or not they had exercised during exposure (Wigaeus et al. 1981). In a group of subjects exposed to acetone vapors for about 6 hours, urinary levels of acetone peaked within the first hour after exposure to 1.8 mg/dL at 250 ppm, 2.9 mg/dL at 500 ppm, and 5.3 mg/dL at 1,000 ppm and declined rapidly post-exposure to control levels within 24, 32, and 48 hours, respectively (Matsushita et al. 1969b). In subjects exposed to 250 ppm for 6 hours/day for 6 days either at rest or during exercise, the urinary levels returned to pre-exposure levels by the next morning each day and within 48 hours after the last exposure day, regardless of whether or not they had exercised (Matsushita et al. 1969a). However, in subjects exposed to 500 ppm 6 hours/day for 6 days, the level of acetone in the urine fell each day, but not to pre-exposure baseline levels. After the last day of exposure, urinary levels returned to baseline levels within 3 days. Baseline urinary levels of acetone in these subjects were about 0.1 mg/dL. Therefore, the rate of urinary clearance is dependent on the magnitude of exposure.

Acetone can also be detected in urine after oral exposure. In a male patient who was admitted to the hospital in a comatose condition after ingesting sake (alcoholic beverage) and liquid cement containing 18% acetone (231 mg/kg), urinary clearance of acetone was followed, but after he had been subjected to gastric lavage (Sakata et al. 1989). Urine levels of acetone decreased gradually from 123 µg/mL at 5 hours after ingestion to about 61 µg/mL at 19 hours. Acetone then disappeared more rapidly from the urine.

Formic acid was detected in the urine of rats collected for 7 days after exposure to 62,000 ppm acetone in air, and was excreted at a rate of 344 µg formic acid/hour, compared with controls that excreted formic acid at a rate of 144 µg/hour (Hallier et al. 1981). The authors concluded that the low rate of formic acid excretion by rats suggests that 24 hours is an insufficient period of time for following formic acid excretion in order to biomonitor acetone exposure in humans.

Blood levels of acetone can also be useful for exposure monitoring, but blood sampling is less desirable because it is more invasive. In a group of 110 male workers exposed to acetone for an average of 14.9 years, blood samples were collected before work on the first day and at the end of work on the second day (Fujino et al. 1992). The breathing zone concentrations of acetone were measured for each individual with personal monitors and ranged from 0 to about 1,200 ppm, with most concentrations between 100 and 500 ppm. The average blood concentration before exposure on the first day was 3.80 mg/L. Blood levels at the end of the workshift (range of about 2 to 225 mg/L, average not reported) correlated strongly with exposure concentration (r=0.65). It was estimated that the blood concentrations corresponding to the current ACGIH TLV for short-term exposure to acetone of 750 ppm and to the Japan Association of Industrial Health acceptable concentration of 200 ppm were 118 and 41.4 mg/L, respectively. Subjects exposed to 100 or 500 ppm for 2 or 4 hours had a blood acetone clearance half-life of 3 hours (DiVincenzo et al. 1973). The rate of blood elimination was constant regardless of blood acetone concentration. In volunteers exposed to 237 ppm acetone, blood levels of acetone averaged 2.0 µg/mL preexposure, 9.0 µg/mL after 2 hours of exposure, 15.3 µg/mL after 4 hours of exposure, 11.9 µg/mL at 90 minutes postexposure, and 1.5 µg/mL at 20 hours postexposure (Dick et al. 1989). Therefore, elimination of acetone from blood was complete 20 hours after exposure. Results were similar for subjects exposed to acetone vapors for 6 hours (Matsushita et al. 1969b). Maximum blood levels of acetone achieved and blood clearance of acetone were exposure concentration related, but not in direct proportion. At an exposure level of 250 ppm, the maximum blood level was 2 mg/dL and returned to baseline levels within 24 hours. At an exposure level of 500 ppm, the maximum blood level was 4.7 mg/dL and returned to baseline levels within 32 hours. At an exposure level of 1,000 ppm, the maximum blood level of 6.0 mg/dL returned to baseline levels within 48 hours. In subjects exposed 6 hours/day for 6 days, maximum blood levels on each day were similar to those seen in the subject exposed only 1 day (Matsushita et al. 1969a). Blood levels returned to baseline levels on the morning after exposure on each day when the exposure concentration was 250 ppm. With an exposure concentration of 500 ppm, however, blood levels declined each day, but not to baseline levels. As with urinary clearance, blood clearance of acetone at the end of the 6-day exposure period returned to baseline within 2 days at 250 ppm and within 3 days at 500 ppm. Baseline blood levels of acetone in these subjects were about 0.1 mg/dL. In subjects exposed to 242 or 542 ppm for 2 hours, the arterial blood concentration 1 hour post-exposure plotted as a function of total uptake gave a linear relationship, indicating that an arterialized capillary sample during or after exposure may be useful for exposure monitoring (Wigaeus et al. 1981). In humans exposed to acetone up to 1,250 ppm for up to 7.5 hours/day in a complex protocol for up to 6 weeks, the concentration of acetone in venous blood was directly related to the vapor concentration and duration of exposure and inversely related to the time elapsed following exposure (Stewart et al. 1975). Using a physiologically-based pharmacokinetic model, Leung and Paustenbach (1988) calculated a biological exposure index of 35 mg acetone/L blood for occupational exposure. The authors reported a baseline acetone blood level of 2 mg/L. This value is in agreement with baseline levels determined in other studies: 0.016 mM (0.93 mg/L) (Gavino et al. 1986), 0.03 mmol/L (1.74 mg/L) (Trotter et al. 1971), and 2,100 ppb (2.1 mg/L) (Ashley et al. 1992).

Similar rates of blood acetone clearance occur after oral exposure. In a patient admitted to the hospital in a comatose condition after ingesting liquid cement containing 18% acetone (231 mg/kg), the plasma level of acetone was 110 µg/mL at 5 hours after ingestion and declined to 65 µg/mL at 18 hours, to 60 µg/mL at 20 hours, and to <5 µg/mL at 48 hours (Sakata et al. 1989). The gastric contents of a patient were analyzed using infrared spectrophotometry and found to contain 1 mL acetone/100 mL (Fastlich 1976). This analytical method was developed to detect volatile solvents in gastric contents due to accidental ingestion of these solvents.

Acetone has been identified in breast milk of lactating women (Pellizzari et al. 1982).

3.3.2. Biomarkers of Effect

The most consistently observed effect of acetone exposure in animals is the induction of microsomal enzymes, particularly of CYP2E1 (see Sections 2.21, 3.1.3, and 3.4). The enzyme induction has been associated with increased liver weights and hepatocellular hypertrophy due to the increased protein content (NTP 1991). Acetone itself is only moderately toxic to the liver of animals, as most studies have found no clinical or histological evidence of liver damage. However, increased levels of serum alanine aminotransferase beyond the expected range, which constitutes clinical evidence of liver damage, have been found in rats in one study (American Biogenics Corp. 1986). CYP2E1 is associated with the metabolism of acetone itself, but acetone is not metabolized to toxic intermediates (see Section 2.3). However, the induction of this enzyme by acetone is the mechanism by which acetone potentiates the hepatotoxicity, nephrotoxicity, genotoxicity, and perhaps the reproductive and hematological toxicity of other chemicals (see Section 2.6). CYP2E1 can be induced by a variety of other factors, such as exposure to ethanol, fasting, and experimental diabetes (Johansson et al. 1986; Puccini et al. 1990); therefore, the induction is not specific to acetone. Moreover, the detection of enzyme induction might require invasive methods, such as liver biopsy.

Exposure of animals to acetone has resulted in degeneration of apical microvilli in renal tubules (Brown and Hewitt 1984) and enhancement of nephropathy commonly seen in aging rats (NTP 1991), but these effects have not been associated with increased levels of blood urea nitrogen.

As is typical of many organic solvents, acetone is irritating to respiratory mucosa, the skin, and eyes. Acetone exposure can also result in such nonspecific narcotic effects such as headache, dizziness, lightheadedness, confusion, unconsciousness (DiVincenzo et al. 1973; Matsushita et al. 1969a, 1969b; Nelson et al. 1943; Raleigh and McGee 1972; Ross 1973), some neurobehavioral and hematological effects (Dick et al. 1989; Matsushita et al. 1969a; Stewart et al. 1975), and perhaps menstrual disorders (Stewart et al. 1975). In addition, patients who had hip casts applied with acetone as the setting fluid became nauseous, vomited blood, and had a strong odor of acetone in the breath. These symptoms were associated with the subsequent development of unconsciousness (Harris and Jackson 1952; Strong 1944). The detection of a strong acetone odor on the breath and nausea could alert physicians to the development of more serious sequelae, such as gastrointestinal hemorrhage and narcosis.

Because acetone is a ketone, acetone exposure can lead to ketosis and other diabetes-like symptoms in humans (Gitelson et al. 1966) and to reduced insulin-stimulated glucose oxidation in animals (Skutches et al. 1990). Again, the detection of a strong odor of acetone on the breath, or high levels of acetone in blood or urine can alert physicians to these effects.

In male rats, acetone exposure resulted in anemia as detected by hematological parameters (American Biogenics Corp. 1986; NTP 1991), and in increased testes weight, decreased sperm motility, caudal and epididymal weight, and increased incidences of abnormal sperm (NTP 1991). Hematological tests and tests for sperm motility and abnormalities could be used to screen humans for possible hematological and fertility effects.

Dermal exposure of humans to acetone irritated the skin, which when examined by light and electron microscopy, showed signs of degenerative changes in the epidermis (Lupulescu and Birmingham 1976; Lupulescu et al. 1972, 1973). Decreased protein synthesis was also found (Lupulescu and Birmingham 1975). Overt signs of skin irritation could alert physicians to possible degenerative changes. Allergic reactions to acetone can be detected by patch testing (Tosti et al. 1988).

As most of the effects from acetone exposure are not specific to acetone, there is no reliable biomarker of effect that can be used to detect or screen for possible effects from exposure to acetone at levels reasonably likely to occur outside the workplace or from accidental ingestion.