Journal ot Analytical loxJcology, Vol. ,'4, Januarylreoruary zuuu
Elimination Half-Life of Acetone in Humans:
Case Reportsand Review of the Literature
A . W . Jones
Departmentof Forensic Toxicology, UniversityHospital, 581 85 Link6ping, Sweden
I Abstract
[
Two instancesof finding abnormally high concentrations of acetone
in urine (0.10 g/dL and 0.052 g/dL) without any measurable amounts
of ethanol (< 0.005 g/dL) or isopropanot (< 0.005 g/dL) prompted a
survey of the elimination kinetics of isopropanol and its metabolite
acetone in humans. In a hospital patient who had ingesteddenatured
alcohol, the elimination half-life (t,~,) of acetone during detoxification
was 27 h and not 3-5 h as reported by other workers. Several other
literature reports of individualswho had ingested isopropanol as well
as controlled studiesafter administration of moderate amounts of
acetone and/or isopropanolsupport the notion of a long elimination
half-life of 17-27 h for acetone compared with a t,~ of 1-3 h for
isopropanol.
Introduction
Acetone is the most abundant endogenous volatile organic
compound in humans (1-3). Forensic toxicologists usually
encounter high concentrations of acetone in body fluids whenever individualsingest isopropanol (rubbing alcohol) for intoxication purposes, because ketones are the proximate metabolites of
secondary alcohols (4,5). However,abnormally high concentrations of acetone might occur in the blood, breath, and urine of
those suffering from ketoacidosis caused by metabolic diseases
such as diabetes mellitus (type I and type II) or during starvation
(6--8). When carbohydrate reserves are depleted, the body derives
much of its energy from the breakdown of fat, and ketone bodies
(l~-hydroxybutyrate,acetoacetate, and acetone) are produced in
excess under these circumstances (9). Indeed, some recent
research results suggest that acetone might be involved in the
conversion of fat to carbohydrate during prolonged periods of
fasting (10). In a large survey of the concentration of acetone in
venous blood samples from type I diabetics (N = 256), healthy
blood donors ~ = 288), and drunk drivers (/V= 500), the average
concentration was very low, 0.2--0.3 mg/dL, and the highest level
was 6.2 mg/dL (11).
cides, samples of urine were obtained from the suspects at about
12 h and 33 h after the crimes were committed. Accordingto the
toxicology reports, one urine specimen contained 0.10 g/dL
acetone, but the results for ethanol and isopmpanolwere negative
(< 0.005 g/dL).The urine also contained oxazepam, nordiazepam
and carboxy-THC. The urine specimen from the other murder
suspect contained 0.052 g/dL acetone, whereas ethanol,
isopropanol, and other drugs were negative. Neither of the
murder suspects was diabetic, and reliable information about
what they had eaten before being apprehended by the police was
lacking. The police required an explanation for the unusually
high concentrations of acetone in the urine samples because
people normally do not drink this solvent for intoxication
purposes. No evidence existed to suggest that the urine specimens had been contaminated with solvents during collection or
after arrival at the forensic laboratory.
Both of the murder suspects admitted drinking alcohol before
the crimes were committed. Indeed, postmortem toxicology on
one of the victims showed blood and urine ethanol concentrations of 0.24 g/dL and 0.29 g/dL, respectively, blood and urine
isopropanol concentrations of 0.045 g/dL and 0.023 g/dL, respectively, and blood and urine acetone concentrations of 0.008 g/dl~
and 0.005 g/dL, respectively. No drugs were identified in body
fluids from the murder victim. The relativelylow concentration ot
acetone compared with isopmpanol in femoral vein blood and the
fact that the urine/blood ratio of isopropanol was < 1.0 suggesl
Acetone
r..
0
0.10
.......
tl/a: 27 h
I=
$
0
U
0 .0 1
E
M
el
0.001
0
10
20
30
40
50
60
Time (h)
Case Histories
During routine police investigations of two unrelated homi8
Figure 1. Concentration-time profiles of acetone and isopropanol in one
male subject who was admitted to hospital for detoxification. The tl~ of
acetone elimination was estimated as 27 h.
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission.
Journal of Analytical Toxicology, Vol. 24, January/February 2000
that the person was killed shortly after starting to drink some
kind of denatured alcohol laced with isopropanol. In the other
murder investigation,an elderly couple were killed by a mentally
disturbed man who had admitted drinking denatured alcohol
before the crime was committed. Forensic toxicologyin the victims showed neither alcohol nor drugs present in body fluids.
Problem drinkers and alcoholics in Sweden are known to drink
denatured alcohol as reported earlier in drunk drivers (12,13).
A male subject (28 years of age) was admitted to the hospital for
detoxification, and a plasma specimen contained 0.039 g/dL
ethanol, 0.065 g/dL isopropanol, and 0.062 g/dL acetone with
traces of methyl ethyl ketone also present. Figure 1 shows a plot
of the concentration-time profiles of isopropanol and acetone in
four plasma samples obtained from this same man during 40 h
before he was discharged from the hospital. Clearlythe elimination half-life t,,2 of acetone is much longer than that of isopropanol, and the t,,2of acetone was estimated as being 27 h. Too
few blood samples were available to permit estimating the t,,2of
isopropanol, but it was obviousthat the rate of elimination of this
secondary alcohol was considerably faster than its metabolite
acetone.
Discussion
Isopropanol is converted into acetone by oxidation with class I
isoenzymes of hepatic alcohol dehydrogenase, and the acetone
produced is then mainly excreted unchanged in breath and urine
and to some extent oxidized by cytochrome P450-enzymes, but
this is a relatively slow detoxification mechanism (14).
Accordingly, the elimination kinetics of acetone should not
interfere with the kinetics of the parent drug isopropanol because
different metabolic pathways are involved.The concentrations of
ethanol in urine specimens from the murder suspects were negative because metabolism occurred during the time before they
were apprehended by the police. In 12 h, a person's blood-ethanol
concentration could decrease by 0.18 g/dL, assuming an average
burn-off rate of 0.015 g/dL/h.
Baselt and Cravey (15) give the elimination half-life (t,,~)of acetone as 3-5 h, whereas the corresponding t,,2 of isopropano] is
given as 2.5-3 h. Because the half-lives of parent drug (isopropanol) and metabolite (acetone)are the same order of magnitude, it is surprising that neither of the urine specimens from the
murder suspects contained any measurable amounts of isopropano] (< 0.005 g/dL). The abnormally high concentration_of
acetonein urine without any isopropanolsuggestsvastly different
half-lives for these two organic volatile substances.Indeed, this
conclusion is supported by the results in Figure i for a person
who had consumed denatured alcohol The elimination half-life
of acetonewas estimated as 27 h.
The first controlled studies of the pharmacokinetics of acetone
in humans were reported by Erik M.P. Widmark as part of his
doctoral thesis (16). Several papers dealing with the disposition
and fate of acetone in the body were subsequently published in
international journals (17,18). In one experiment, Widmark
drank 16 g of acetonesolvent diluted with 500 mL water and took
blood samples for determination of acetone at various times for
up to 24 h later. Widmark found that acetone was eliminated from
blood by first order kinetics and the elimination rate constant (kl)
was 0.000648 rain-1, which corresponds to a t,,2of 17.7 h (t,,2 =
0.69/kl). This value is significantlydifferent from the t,,2of 3-5 h
reported by Baselt and Cravey(15), which however cites the work
of Widmarkto support the t,,2of acetone reported as 5 h. However,
on closer examination it seems that this experiment involved
acetone pharmacokinetics in a rabbit (kl = 0.00215 rain-1, t,,2=
5.3 h) and not a human being (19).Widmark'sexperiments on the
pharmacokinetics of acetone involved both oral and rectal
administration of the drug, which ensures equilibrium distribution of acetone in the total body water, which is one
prerequisite for obtaining reliable concentration-time data for
calculating the elimination rate constant and half-life (18,19).
In two individualswho drank isopropanol, the elimination halflife was reported as 2.6 h and 3.1 h, although the corresponding
half-lives of acetone were not reported. However, it was mentioned that the concentration of acetone remained elevatedfor 37
h in one subject (20). In another instance of isopropanol intoxication, the elimination half-life of acetone was given as 22.4 h
compared with 6.4 h for isopropanol (21). In a recently reported
controlled study of the disposition kinetics of isopropanol, four
volunteers drank 0.6 mL/kg of 70% isopropanol diluted to 240
mL with water within 5 min (22). The concentrations of acetone
and isopropanol were then determined in serum by two independent analytical methods. Although the main focus of the article
was not pharmacokinetics of acetone and isopropanol, the elimination rate constants were reported and these converted to halflives of 14.4-20 h (mean 17 h) for acetone and 0.81--0.94 h (mean
0.9 h) for isopropanol.
Pappas et al. (23) presented both isopropanol and acetone
serum concentration-time profiles for five patients who had
ingested rubbing alcohol (isopropanol). The results showed
unequivocallythat acetone had a much longer elimination halflife than isopropanol.The apparent half-lifeof isopropanol ranged
from 2.9 to 16.2 h compared with 7.6-26.2 h for acetone.
Conclusions
The above case reports and the review of the literature make it
obvious that the t,,, of acetone is much longer than 3-5 h (15).
The pioneer work by Widmark (16-19), as well as case reports of
subjects poisoned with isopropanol (20,21), including the one
presented here (t,,2 = 27 h), and the careful study by Monaghan
et al. (22) show convincingly that the elimination kinetics of
acetone in humans has a t,,~of about 17-27 h.
References
I. B. Krotoszynaski,G. Gabriel, H. O'Neill, and M.ffA. Claudio.
Characterizationof human expired air: a promising investigative
and diagnostictechnique.J. Chromatogr. $ci. IS: 239-244(1977).
2. J.P.Conkle,B.J.Camp,and B.E.Welch.Tracecompositionof human
respiratorygas.Arch. Environ. Health 30:290-295 (1975).
3. B.O.Janssonand B.T.Larsson.Analysisof organiccompoundsin
Journal of Analytical Toxicology,Vol. 24, January/February2000
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
10
human breath by gas chromatography-mass spectrometry. J. Lab.
Clin. Med. 74:961-966 (1969).
C.B. Alexander, A.J. McBay, and R.R Hudson. Isopropanol and
isopropanol deaths--ten years experience. J. Forensic Sci. 27:
541-548 (1982).
RG. Lacouture, S. Wason, A. Abrams, and F.H. Lovejoy. Acute is(>
propyl alcohol intoxication. Am. J. Med. 75:680-686 (1983).
W. Fosterand J.D. McGarry. The metabolic derangements and treatment of diabetic ketoacidosis. N. Engl. ]. Med. 309:159-169
(1983).
J. Henderson, B.A. Karger, and G.A. Wrenshall. Acetone in the
breath: a study of acetone exhalation in diabetic and nondiabetic
human subjects. Diabetes I: 188-193 (1952).
8. Crofford, R.E. Mallard, R.E. Winton, N.L. Rogers, J.C. Jackson,
and U. Keller. Acetone in breath and blood. Trans.Am. Clin. Climat.
Assoc. 88:128-139 (1977).
J.D. McGarry and D.W. Foster. Regulation of ketogenesis and clinical aspects of the ketonic state. Metabolism 21:471-489 (1972).
J.M. Argil~s. Has acetone a role in the conversion of fat to carbohydrate in mammals? TrendsBiochem. Sci. 11:61-63 (1986).
A.W. Jones, A. Sagarduy, E. Ericsson, and H.J. Arnqvist. Concentrations of acetone in venous blood samples from drunk
drivers, type-I diabetic outpatients, and healthy blood donors.
J. Anal ToxicoL 17:182-185 (1993).
A.W. Jones, M. Lund, and E. Andersson. Drinkingdrivers in Sweden
who consume denatured alcohol preparations: an analytical toxicological study. J. Anal ToxicoL 13:199-203 (1989).
A.W. Jones, L. Andersson, and K. Berglund. Interfering substances
identified in the breath of drinking drivers with Intoxilyzer 5000S.
J. AnaL Toxicol. 20:522-527 (1996).
M.J. Ellenhorn and D.G. Barceleoux. Medical Toxicology;
Diagnosis and Treatment of Human Poisoning. Elsevier, New York,
NY, 1988.
15. R.C. Baselt and R.H. Cravey. Disposition of Toxic Drugs and
Chemicals in Man, 4th ed. Chemical Toxicology Institute, Foster
City, CA, 1995, pp 7 and 405.
16. E.M.R Widmark. Acetonkoncentrationen i blod, urin, och alveol~rluft. Doctoral Thesis, University of Lund, 1917, pp 1-181.
17. E.M.R Widmark. Studies in the acetone concentration in blood,
urine, and alveolar air. II1: The elimination of acetone through the
lungs. Biochem. J. 14:379-394 (1920).
18. E.M.R Widmark. Studies on the concentration of indifferent narcotics in blood and tissues. Acta Med. Scand. 52' 87-164 (t920).
19. E.M.R Widmark. Principles and Applications of Medicolegal
Alcohol Determination. Biomedical Publications, Davis, CA, 1982,
p94.
20. D.R. Daniel, B.H. McAnalley, and J.C. Garriott. Isopropyl alcohol
metabolism after acute intoxication in humans. J. Anal ToxicoL 5:
110-112 (1981).
21. M. Natowic.z, J. Donahue, L. Gorman, W. Kane, J. McKissicj, and
L. Shaw. Pharmacokinetic analysis of a case of isopropanol intoxication. Clin. Chem. 31:326-328 (1985).
22. M.S. Monaghan, K.M. Olsen, B.H. Ackerman, G.L. Fuller,
W.H. Porter, and A.A. Pappas. Measurement of serum isopropanol
and the acetone metabolite by proton nuclear magnetic resonance:
application to pharmacokinetic evaluation in a simulated overdose
model. J. ToxicoL Clin. ToxicoL 33:141-149 (1995).
23. A.A. Pappas, B.H. Ackerman, K.M. Olsen, and E.H. Taylor.
Isopropanol ingestion: a report of six episodes with isopropanol and
acetone serum concentration data. J. Toxicol. Clin. ToxicoL 29:
11-21 (1991).
Manuscript received December 21, 1998;
revision received March 16, 1999.