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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Appendixes

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 This page intentionally left blank.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 1 Acetone Hector D. Garcia, Ph.D. NASA-Johnson Space Center Toxicology Group Habitability and Environmental Factors Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Acetone is a clear, colorless, highly volatile, flammable liquid with a sweet, fruity aroma (odor threshold = 13 parts per million [ppm]) and excellent solvent properties. It forms explosive mixtures with air or oxygen (see Table 1-1). OCCURRENCE AND USE Acetone is a product of normal metabolism in humans and animals. It is produced during the breakdown of fat and is used in the synthesis of glucose and fat. Trace amounts are detectable in normal human blood (7.0-14.0 micromoles per liter [µmol/L] = 0.4-0.8 micrograms per milliliter [µg/mL]) and urine (4.0-35.0 µmol/L = 0.2-2.0 µg/mL) (Rowe and Wolf 1963; Wang et al. 1994; de Oliveira and Pereira Bastos de Siqueira 2004). Endogenous concentrations of acetone in the blood have been reported up to 10 µg/mL, and concentrations during diabetic ketoacidosis have ranged from 100 to 700 µg/mL (Gamis and Wasserman 1988). Data from a National Institute for Occupational Safety and Health (NIOSH) report (Stewart et al. 1975) on acetone suggest that normal blood acetone concentrations in women (1.8-4.2 mg% = 18-42 µg/dL) may be two to three times higher than in men (0.5-1.4 mg% = 5-14 µg/mL), but no other reports could be found to confirm this. High acetone concentrations in serum and breath are often indicative of altered metabolic states including diabetes, vitamin E deficiency, and fasting (NTP 1991).

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 1-1 Physical and Chemical Properties of Acetonea Formula C3H6O   Chemical Name Acetone Synonyms Propanone, 2-propanone, dimethylketone, dimethyl formaldehyde, dimethylketal, ketone propane, beta-ketopropane, methyl ketone, pyroacetic acid, pyroacetic ether CAS registry no 67641 Molecular weight 58.09 Boiling point 56.48°C Melting point −94.6°C Density 0.7972 g/cc (at 15°C) Vapor Pressure 400 mm at 39.5°C, 200 mm at 25°C Vapor density 2 (air = 1) Solubility Infinitely soluble in water; miscible with alcohol, dimethylformamide, chloroform, most oils, and ether Lower Explosive Limit 2% (in air) Upper explosive Limit 13% (in air) Odor Threshold (in air) 13 ppm; 47 mg/m3 Odor Threshold (in water) 20 ppm; 20 mg/L aData from HSDB 2006. Acetone is not routinely used in spacecraft during flight but may be part of in-flight scientific experiments. Acetone is found in the spacecraft atmosphere on almost every mission at concentrations up to 8 ppm in Skylab (Liebich et al. 1975) and up to 1.2 ppm during shorter Shuttle missions—probably from crew metabolism and offgassing. TOXICOKINETICS AND METABOLISM Much of the data in the literature regarding acetone toxicokinetics and metabolism involves exposure by inhalation, but because of the general distribution of acetone in body water and its relatively slow metabolism, as described below, the data should hold true for acetone exposures by ingestion as well. Absorption Acetone is rapidly and almost totally absorbed from the stomach and is also absorbed by inhalation, by mucous membranes, and, to some

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 degree, through the skin. The rate of absorption of ingested acetone depends on the amount of food in the stomach. In one subject, peak blood levels of acetone were seen 10 min after ingestion of acetone on an empty stomach, while acetone ingested about 10 min after a meal was more slowly absorbed, with lower peak levels achieved at 48-59 min after ingestion (Widmark 1919). Distribution No studies were found on the distribution of acetone after ingestion. In studies of the inhalation toxicokinetics of acetone in rats, Hallier et al. (1981) found that acetone is mainly, but not exclusively, distributed within the body water compartment under conditions of negligible metabolism (saturation of metabolizing enzymes). The kinetics of the exhalation of acetone was strictly monoexponential, indicating that it does not distribute into a “deep compartment”—that is, one from which it is released only slowly. Also, acetone is water soluble and will not accumulate in adipose tissue. Mice exposed to 2-[14C]-acetone vapor (500 ppm) for periods of 1 h to 5 days (d) were examined for the tissue distribution of radioactivity (Löf et al. 1980; Wigaeus et al. 1982). The amount of radioactivity in tissues increased as the exposure time increased from 1 to 6 h but increased only slightly or not at all in all tissues except adipose tissue at exposure times greater than 6 h (12 h, 24 h, and 5 d) (Wigaeus et al. 1982). Liver and pancreas showed the highest concentration of radioactivity; the lowest concentrations were in muscles and white adipose tissue. After 3 or 5 d of inhalation exposure (6 h/d) to 500 ppm 2-[14C]-acetone vapor, the radioactive concentration in mouse tissues was highest in brown adipose tissue, followed by liver and pancreas (Wigaeus et al. 1982). Only about 10% of the radioactivity in the liver was unchanged acetone. Metabolism Ramu et al. (1978) in a case report involving the ingestion of nail polish remover by an alcoholic estimated that humans can metabolize acetone at a rate probably not exceeding 1 g/h, but none of the metabolites were identified. On a gram per kilogram basis, the rate of acetone metabolism in humans has been reported to be about half that the rat

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 (Haggard et al. 1944), with metabolism being nonlinear and saturable. Haggard et al. documented a zero-order elimination rate in rats of 13 milligrams per kilograms per hour (mg/kg/h) at a blood acetone concentration of 0.2 g/deciliter (dL). In a 10-d study of female rats, tolerance was reported to develop whereby the effects of inhaled acetone on the inhibition of avoidance behavior and escape response in rats became weaker upon repeated administration (Goldberg et al. 1964), probably because of an induction of metabolic enzymes in the liver. Several studies in rats have shown that acetone can be metabolized by three separate gluconeogenic pathways, with the first step in all cases being the hydroxylation of one of the methyl groups by acetone monooxygenase to form acetol (NTP 1991). One of the intermediates in the metabolism of acetone to carbon dioxide is formate, which in humans, is metabolized more slowly than in rodents. Elimination The main route of excretion of acetone is via the lungs—regardless of the route of exposure—with very little excreted in the urine (Ramu et al. 1978; Wigaeus et al. 1981; Gamis and Wasserman 1988). About half of the acetone is exhaled unchanged in humans, and the other half is exhaled as carbon dioxide produced from the metabolism of acetone (Wigaeus et al. 1982). Several different estimates of the half-life of acetone in blood have been reported, with the reported half-life increasing with the dose of acetone (DiVincenzo et al. 1973; Ramu et al. 1978; Wigaeus et al. 1981; Gamis and Wasserman 1988). In acute intoxications in adult humans, the half-life of acetone in plasma has been estimated at approximately 31 h and is consistent with a first-order elimination process (Ramu et al. 1978). A more recent estimate of the elimination plasma half-life of acetone in humans is 18 h (Sakata et al. 1989). Jones reported half-lives for acetone in the blood and urine ranging from 3-27 h, but some of the measurements were from ingestion of isopropanol or denatured alcohol rather than acetone itself (Jones 2000). A half-life of only 3.9 h was estimated for volunteers inhaling acetone at 250 ppm for 4-h and assuming first-order kinetics (Dick et al. 1988). A case report of a 42-year-old man who intentionally swallowed 800 mL of acetone reported acetone concentrations of 2,000 mg/L in serum and 2,300 mg/L in urine and an elimination half-life of 11 h with sequelae-free survival after aggressive treatments including multiple gastric lavages, hyperventilation, hemofiltration, forced diuresis and hydration (Zettinig et al.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 1997). Two studies on inhaled acetone (Matsushita et al. 1969b and Di-Vincenzo et al. 1973, as cited in OSHA 1989) suggest that chronic intermittent exposure to high enough doses of acetone on a daily basis can lead to the bioaccumulation of acetone. Based on Ramu et al.’s (1978) estimate of the maximum metabolism rate in humans (1 g/h), accumulation in the blood should be seen for dose rates exceeding about 24 g/d. On a milligram per kilogram basis, Haggard et al.’s (1944) estimate of the metabolic rate of acetone in rats implies that dose rates exceeding about 11 g/d in humans could lead to an accumulation of acetone in a 70-kg person. TOXICITY SUMMARY Systemic effects reported in humans and animals after oral or inhalation exposure to acetone are described below and in Table 1-2. At high doses, whether by inhalation or ingestion, manifestations of acute acetone toxicity in humans primarily involve central nervous system (CNS) depression that ranges from lethargy, slurred speech, and ataxia to stupor, coma, and respiratory depression (Ross 1973; Ramu et al. 1978; Gamis and Wasserman 1988). Other adverse effects of high doses include vomiting, hematemesis, excessive thirst, polyuria, hyperglycemia, and occasionally, metabolic acidosis (probably because of the metabolism of acetone to formate) (Ross 1973; Ramu et al. 1978; Gamis and Wasserman 1988). One Soviet investigator reported that four individuals acutely exposed (one by inhalation and three orally) to unspecified concentrations and amounts of acetone developed liver lesions and, in two of the orally intoxicated individuals, mild renal lesions (Mirchev 1977). The quality of this case study report was not evaluated, because it was written in Bulgarian with only the abstract translated into English; thus, it could not be determined if the four patients had also been exposed to other agents such as alcohol or may have had pre-existing lesions of the liver or kidneys. Acute and Short-Term Exposures General Humans who ingest up to 20 mL of acetone do not show any adverse effects (Gosselin et al. 1984). Ingestion of 200 mL, however, can

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 1-2 Toxicity Summary     Concentration Exposure Duration Species Effects Reference Effects in Humans     ~200 mL pure acetone (~2,241 mg/kg) Bolus Human Deep coma; red and swollen throat and erosion in soft palate and entrance to esophagus; disturbance of gait 6 d after ingestion; diabetes-like condition 4 wk after ingestion with hyperglycemia, polyuria, and excessive thirst Gitelson et al. 1966 Unknown amount of acetone; presumed ingestion by an alcoholic woman 1 wk? Human Lethargy, minimal responsiveness; blood acetone concentration = 0.25 g/dL; pharynx was not red or swollen, nor were there erosions of the soft palate; recovery was gradual over 3-4 d; acetone half-life = 31 h Ramu et al. 1978 Estimated 6 oz of nail polish remover (65% acetone, 10% isopropanol) Bolus Human (30 mo old) Sedated and nonresponsive; no reflexes; generalized tonic-clonic seizure; serum acetone concentration = 445 mg/dL; gradual recovery over 4 d with no adverse sequelae; acetone half-life = 19 h initially, then 13 h in the later stages of recovery Gamis and Wasserman 1988 >12,000 ppm in air in a pit 2 min-4 hr Human (n = 8) Throat and eye irritation, leg weakness, chest tightness, headache, dizziness, confusion, unconsciousness, vomiting; gradual, dose-dependent recovery Ross 1973

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Effects in Animals         100,000 ppm in drinking water 14 d F344/N rats, male and female; B6C3F1 mice, male and female LOAEL for bone marrow hypoplasia in male rats; LOAEL for emaciated appearance in rats; LOAEL for decreased weight gain in male mice; decreased water consumption and weight gain in rats and male mice; liver hypertrophy in male and female mice Dietz et al. 1991; NTP 1991 Rats   male: 6.9 g/kg/d   female: 8.6 g/kg/d   Mice     male: 10.3 g/kg/d     female: 12.7 g/kg/d     50,000 ppm in drinking water 14 d F344/N rats, male and female; B6C3F1 mice, male and female LOAEL for liver hypertrophy in female mice; NOAEL for bone marrow hypoplasia in males; LOAEL for decreased water consumption in rats and mice; LOAEL for decreased weight gain in rats; increased kidney weights in rats Dietz et al. 1991; NTP 1991 Rats   male: 4.3 g/kg/d   female: 4.4 g/kg/d   Mice     male: 6.3 g/kg/d     female: 8.8 g/kg/d     20,000 ppm in drinking water 14 d F344/N rats, male and female LOAEL for increased relative kidney weight in female rats; LOAEL for increased relative liver weight in male and female rats Dietz et al. 1991; NTP 1991 male: 2.6 g/kg/d   female: 2.3 g/kg/d   20,000 ppm in drinking water (3.9-5.5 g/kg/d) 14 d B6C3F1 mice, male and female LOAEL for liver hypertrophy in male mice and NOAEL for liver hypertrophy in female mice Dietz et al. 1991; NTP 1991

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Concentration Exposure Duration Species Effects Reference 10,000 ppm in drinking water 14 d F344/N rats, male and female; B6C3F1 mice, male and female NOAEL for liver hypertrophy Dietz et al. 1991; NTP 1991 Rats   male: 1.6 g/kg/d   female: 1.5 g/kg/d   Mice     male: 1.6 g/kg/d     female: 3.0 g/kg/d     5,000 ppm in drinking water 14 d B6C3F1 mice, male and female LOAEL for increased liver weight Dietz et al. 1991; NTP 1991 Mice   male: 1.0 g/kg/d   female: 1.6 g/kg/d   50,000 ppm in drinking water (3.1-3.4 g/kg/d) 13 wk F344/N rats, male and female LOAEL for increased relative kidney weight in male rats; LOAEL for mild spermatogenic toxicity and increased relative weight of testis; LOAEL for mild leukocytosis in females; decreased water consumption, but no dehydration; mild macrocytic normochromic anemia in male rats; LOAEL for decreased body weight in rats; LOAEL for decreased water consumption in rats Dietz et al. 1991; NTP 1991 50,000 ppm in drinking water (11 g/kg/d) 13 wk B6C3F1 mice, female LOAEL for increased liver and decreased spleen weights in female mice; increased kidney weights; LOAEL for decreased water consumption in mice Dietz et al. 1991; NTP 1991

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 20,000 ppm in drinking water (1.6-1.7 g/kg/d) 13 wk F344/N rats, male and female Decreased erythrocyte counts and hemoglobin concentrations in males; LOAEL for increased relative weight of liver in males and females; LOAEL for increased relative weight of kidney in females; LOAEL for increased severity of nephropathy in males; LOAEL for minimal-to-mild splenic hemosiderosis in males; LOAEL for mild leukocytosis in males Dietz et al. 1991; NTP 1991 20,000 ppm in drinking water (5.9 g/kg/d) 13 wk B6C3F1 mice, female NOAEL for increased liver weight in female mice Dietz et al. 1991; NTP 1991 10,000 ppm in drinking water (0.9 g/kg/d) 13 wk F344/N rats, male NOAEL for mild nephropathy and splenic hemosiderin deposits Dietz et al. 1991; NTP 1991 5,000 ppm in drinking water (0.4 g/kg/d) 13 wk F344/N rats, male LOAEL for decreased reticulocyte counts (macrocytic anemia?) Dietz et al. 1991; NTP 1991 5,000 ppm in drinking water (1.4 g/kg/d) 13 wk B6C3F1 mice, male LOAEL for increased liver weight in males Dietz et al. 1991; NTP 1991 2,500 ppm in drinking water (0.2 g/kg/d) 13 wk F344/N rats, male LOAEL for marginally increased mean corpuscular hemoglobin and mean cell volume (indicative of folate deficiency?), with no change in mean corpuscular hemoglobin concentration (indicative of mild macrocytic normochromic anemia); these effects were not seen in female rats at concentrations below 50,000 ppm Dietz et al. 1991; NTP 1991

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 healthy adults, so protection of very young or sick persons is not required. EPA’s RfD Calculations and Rationale The EPA’s reference dose (RfD) (see Table 1-3) was based on mild nephropathy as the critical effect, as seen only in male rats in the NTP (1991) study: “The data were analyzed using the NOAEL/LOAEL approach using a point of departure of 900 mg/kg-day based on an increased incidence of mild nephropathy. The following UFs are applied to the effect level: 10 for consideration of intraspecies variation (UFH; human variability) [not used in SWEG calculations], 3 (√10) for extrapolation for interspecies differences (UFA; animal to human), 3 (√10) to account for extrapolation from subchronic studies (UFs; subchronic to chronic), and 10 to account for a deficient database (UFD). The total UF = 10 × √10 × √10 × √10 = 1000” (EPA 2003). RATIONALE FOR ACs Acceptable Concentrations (ACs) can be set for the following adverse effects of acetone exposure discussed above: hematologic toxicity (bone marrow hypoplasia and macrocytic anemia) and splenic hemosid- TABLE 1-3 Exposure Limits Set by Other Organizations Organization Exposure Limit (mg/kg/d) Reference Equivalent Drinking Water Concentration (mg/L)a ATSDR 2 (intermediate duration MRL) ATSDR 1994 50 EPA 0.9 (chronic RfD) EPA 2003 2.5 aThe equivalent concentration of acetone in water that would yield the indicated mg/kg/d dose (MRL or RfD) for a 70-kg person drinking 2.8 L of water. Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry; EPA, U.S. Environmental Protection Agency; MRL, minimal risk level—an estimated daily dose likely to be without risk of deleterious noncancer effects for a specified duration of exposure of the human population; RfD, reference dose—an estimated daily dose likely to be without risk of deleterious effects for a lifetime exposure of the human population.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 1-4 Spacecraft Water Exposure Guidelines Duration Concentration (ppm or mg/L) Target Toxicity 1 d 3,500 Bone marrow hypoplasia 10 d 3,500 Bone marrow hypoplasia 100 d 150 Macrocytic anemia 1,000 d 15 Macrocytic anemia erin deposits. ACs that protect against these effects will also protect against more-severe effects such as ataxia, immediate CNS depression, and death. Calculation using the guidelines established by the National Research Council’s (NRC’s) Committee on Toxicology (2000) to determine the highest AC for each major end point and exposure duration is documented below. If exposure data were available for both the concentration of acetone in drinking water and the daily dose (in mg/kg/d) of acetone, the ACs were calculated based on the daily dose. A SWEG value (see Table 1-4) is set for each exposure duration on the basis of the end point that yielded the lowest AC at that exposure duration. The resulting ACs for the various end points are compiled in Table 1-5 and compared. 1-d and 10-d ACs One-d and 10-d ACs can be based on the 4,300 mg/kg/d (50,000 ppm) NOAEL for bone marrow hypoplasia in male rats after 14 d of exposure (Dietz et al. 1991; NTP 1991). Benchmark dose analysis was not appropriate for the bone marrow hypoplasia data because of the dose-response behavior; that is, the only dose at which hypoplasia was seen was the highest dose (100,000 ppm), at which 100% of test animals had hypoplasia. An interspecies UF of 10 is applied to extrapolate from rats or mice to humans. The AC is not adjusted higher for the shorter-exposure durations (1 or 10 d versus 14 d). Thus, for bone marrow hypoplasia, the AC is calculated as follows: Because microgravity induces a reduction in red cells that would be exacerbated by bone marrow hypoplasia, the AC will be reduced by a spaceflight factor of 3. To achieve a dose rate of 430 mg/kg/d for a 70-kg

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 1-5 Acceptable Concentrations (ACs)       UFs ACs (mg/L) End Point Exposure Data Species and Reference Inter- individual To NOAEL Inter- species Exposure Time Spaceflight 1 d 10 d 100 d 1,000 d NOAEL for bone marrow hypoplasia 4,312 mg/kg/d (50,000 ppm); 2 wk; drinking water Rat, male (NTP 1991) 1 1 10 1 3 3,500 3,500 — — NOAEL for macrocytic anemia 200 mg/kg/d (2,500 ppm); 13 wk; drinking water Rat, male (NTP 1991) 1 1 10 0.9 3 — — 150 15 NOAEL for mild nephropathy and splenic hemosiderin 1,700 mg/kg/d (10,000 ppm); 13 wk; drinking water Rat, male (NTP 1991) 1 1 10 0.9 1 — — 2,000 200 SWEG               3,500 3,500 150 15

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 astronaut consuming 2.8 L of water per d, the concentration of acetone in the drinking water would need to be as follows: 100-d ACs Mild macrocytic anemia was reported in male rats receiving acetone for 13 wk at doses above 200 mg/kg/d (acetone concentrations >2,500 ppm) (Dietz et al. 1991; NTP 1991). Above 900 mg/kg/d (10,000 ppm), mild nephropathy and splenic hemosiderosis were reported in male rats. Hepatocellular hypertrophy is considered adaptive. Therefore, ACs were calculated based on NOAELs for anemia, nephropathy, and hemosiderosis. For macrocytic anemia, the AC is calculated as follows: Because microgravity induces a reduction in the number of red cells that would be exacerbated by bone macrocytic anemia, the AC will be reduced by a spaceflight factor of 3. For a 70-kg astronaut consuming 2.8 L of water per d, the concentration of acetone in the drinking water needed to achieve a dose rate of 20 mg/kg/d would be A factor of 90 d/100 d = 0.9 was used to adjust the NOAEL-based AC for the difference in exposure durations between the 90-d rodent data and the 100-d astronaut exposure durations. Thus, for macrocytic anemia, the AC is calculated as follows: For mild nephropathy and splenic hemosiderin, the AC is calculated as follows:

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 For a 70-kg astronaut consuming 2.8 L of water per d, the concentration of acetone in the drinking water needed to achieve a dose rate of 90 mg/kg/d would be as follows: A factor of 90 d/100 d = 0.9 was used to adjust the NOAEL-based AC for the difference in exposure durations between the 90-d rodent data and the 100-d astronaut exposure durations. Thus, for mild nephropathy and splenic hemosiderin, the AC is calculated as follows: The odor and taste of acetone at 4,000 mg/L in drinking water is distinctly noticeable (mild) but not objectionable to all of six male test subjects (H. Garcia, National Aeronautics and Space Administration, Houston, TX, unpublished material, 2004). 1,000-d ACs ACs for 1,000-d exposures were derived by dividing the ACs for 100-d exposures by a factor of 10 for longer-exposure duration. For macrocytic anemia, the AC is calculated as follows: For mild nephropathy and splenic hemosiderin, The odor and taste of acetone at 400 mg/L in drinking water were undetectable to all of six male test subjects (H. Garcia, National Aeronautics and Space Administration, Houston, TX, unpublished material, 2004).

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Reproductive Effects After 4 d of exposure to acetone vapors at 1,000 ppm for 7 h/d, female volunteers experienced premature menstrual periods (Stewart et al. 1975). Other than transient irritation, no other adverse effects were reported (Stewart et al. 1975). The National Aeronautics and Space Administration (NASA) tests female astronauts for pregnancy before flight, and those found to be pregnant are not permitted to fly; therefore, premature menses is not considered an adverse effect and will not be used to set an AC. Spaceflight Considerations Microgravity is known to cause “space anemia,” a decrease in total blood volume and total number of red blood cells but no decrease in the concentration of red blood cells. The mechanism has been shown to involve increased excretion of fluid from plasma into urine and a decrease in the production of erythropoietin and, therefore, decreased production of red blood cells. However, microgravity does not appear to cause any increase in the rate of destruction of red blood cells. Of the effects induced by exposure to acetone, only bone marrow hypoplasia and macrocytic anemia could potentially be exacerbated by known effects of launch, microgravity, or re-entry. Because the mechanisms involved in the control of space anemia are not well known enough to rule out the possibility of additive or synergistic effects with bone marrow hypoplasia and macrocytic anemia caused by acetone exposures, a spaceflight factor of 3 was used to adjust the ACs. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1986. Acetone. Pp. 6-4 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th Ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. American Biogenics Corp. 1986. Ninety-day gavage study in albino rats using acetone. Unpublished study 410-2313. American Biogenics Corp., Decatur, IL. Anderson, P.K., M.R. Woolhiser, and J.M. Waechter. 2004. Acetone: 4-week drinking water immunotoxicity in CD-1 mice. Paper presented at the Soci-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 ety of Toxicology 43rd Annual Conference, March 21-25, 2004, Baltimore, MD. Arena, J.M., and R.H. Drew, eds. 1986. Poisoning: Toxicology, Symptoms, Treatments, 5th Ed. Springfield, IL: Charles C. Thomas, Publisher. ATSDR (Agency for Toxic Substances and Disease Registry). 1994. Toxicological profile for acetone. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Baselt, R.C. 1982. Acetone. Pp. 9-10 in Disposition of Toxic Drugs and Chemicals in Man. Davis, CA: Biomedical Publications. Bruckner, J.V., and R.G. Peterson. 1981. Evaluation of toluene and acetone inhalant abuse. I. Pharmacology and pharmacodynamics. Toxicol. Appl. Pharmacol. 61:27-38. Chieli, E., M. Saviozzi, P. Puccini, V. Longo, and P.G. Gervasi. 1990. Possible role of the acetone-inducible cytochrome P-450IIE1 in the metabolism and hepatotoxicity of thiobenzamide. Arch. Toxicol. 64(2):122-127. Cunningham, J., M. Sharkawi, and G.L. Plaa. 1989. Pharmacological and metabolic interactions between ethanol and methyl n-butyl ketone, methyl isobutyl ketone, methyl ethyl ketone, or acetone in mice. Fundam. Appl. Toxicol. 13:102-109. de Oliveira, D.P., and M.E. Pereira Bastos de Siqueira. 2004. Reference values of urinary acetone in a Brazilian population and influence of gender, age, smoking and drinking. Med. Lav. 95:32-38. Dick, R.B., W.D. Brown, J.V. Setzer, B.J. Taylor, and R. Shukla. 1988. Effects of short duration exposures to acetone and methyl ethyl ketone. Toxicol. Lett. 43:31-49. Dick, R.B., J.V. Setzer, B.J. Taylor, and R. Shukla. 1989. Neurobehavioural effects of short duration exposures to acetone and methyl ethyl ketone. Br. J. Ind. Med. 46:111-121. Dietz, D.D., J.R. Leininger, E.J. Raukman, M.B. Thompson, R.E. Chapin, R.L. Morrissey, and B.S. Levine. 1991. Toxicity studies of acetone administered in the drinking water of rodents. Fundam. Appl. Toxicol. 17:347-360. DiVincenzo, G.D., F.J.Yanno, and B.D. Astill. 1973. Exposure of man and dog to low concentrations of acetone vapor. Am. Ind. Hyg. Assoc. J. 34:329-336. EPA (U.S. Environmental Protection Agency). 2003. Acetone. In Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency, National Center for Environmental Assessment, Washington, DC [Online]. Available: http://www.epa.gov/IRIS/subst/0128.htm [accessed Feb. 24, 2005]. Finkel, A.J. 1983. Acetone. Pp. 210-211 in Hamilton and Hardy's Industrial Toxicology, 4th Ed. Boston: John Wright PSG, Inc. Freeman, J.J., and E.P. Hayes. 1985. Acetone potentiation of acute acetonitrile toxicity in rats. J. Toxicol. Environ. Health 15:609-621.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Freeman, J.J., and E.P. Hayes. 1988. Microsomal metabolism of acetonitrile to cyanide. Biochem. Pharmacol. 37:1153-1159. Gamis, A.S., and G.S. Wasserman. 1988. Acute acetone intoxication in a pediatric patient. Pediatr. Emerg. Care 4(1):24-26. Geller, I., E.M. Gause, H. Kaplan, and R.J. Hartmann. 1979a. Effects of acetone, methyl ethyl ketone and methyl isobutyl ketone on a match-to-sample task in the baboon. Pharmacol. Biochem. Behav. 11:401-406. Geller, I., R.J. Hartmann, S.R. Randle, and E.M.Gause. 1979b. Effects of acetone and toluene vapors on multiple schedule performance of rats. Pharmacol. Biochem. Behav. 11:395-399. Gitelson, S., A. Werczberger, and J.R. Herman. 1966. Coma and hyperglycemia following drinking of acetone. Diabetes 15:810-811. Glatt, J., L. DeBalle, and F. Oesch. 1981. Ethanol- or acetone-pretreatment of mice strongly enhances the bacterial mutagenicity of dimethylnitrosamine in assays mediated by liver subcellular fraction, but not in host-mediated assays. Carcinogenesis 2:1057-1067. Goldberg, M.E., H.E. Johnson, U.C. Pozzani, and F.H. Smyth, Jr. 1964. Effect of repeated inhalation of vapors of industrial solvents on animal behavior. Evaluation of nine solvent vapors on pole-climb performance in rats. Am. Ind. Hyg. Assoc. J. 25:369-375. Gosselin, R.E., R.P. Smith, and H.C. Hodge. 1984. Clinical toxicology of commercial products, 5th ed. Baltimore, MD: Williams & Wilkins. Grant, M. 1986. Acetone. Pp. 41-42. In Toxicology of the Eye, 3rd Ed. Springfield, IL: Charles C. Thomas, Publisher. Haggard, H.W., L.A. Greenberg, and J.M. Turner. 1944. The physiological principles governing the action of acetone together with determination of toxicity. J. Ind. Hyg. Toxicol. 26:133-151. Hallier, E., J.G. Filser, and H.M. Bolt. 1981. Inhalation pharmacokinetics based on gas uptake studies. II. Pharmacokinetics of acetone in rats. Arch. Toxicol. 47:293-304. Hewitt, W.R., H. Miyajima, M.G. Coté, and G.L. Plaa. 1980. Modification of haloalkane-induced hepatotoxicity by exogenous ketones and metabolic ketosis. Fed. Proc. 39:3118-3123. HSDB (Hazardous Substances Data Bank). 2006. Acetone. U.S. National Library of Medicine. [Online]. Available at: http://toxnet.nlm.nih.gov/cgibin/sis/search/f?/temp/~RqiGV0:1 [access September 5, 2006]. Inoue, R. 1983. Acetone and derivatives. Pp. 38-39 in Encyclopedia of Occupational Health and Safety, 3rd Rev. Ed. L. Parmeggiani, ed. Geneva, Switzerland: International Labour Organization. Johansson, I., and M. Ingelman-Sundberg. 1988. Benzene metabolism by ethanol-, acetone-, and benzene-inducible cytochrome P-450 (IIE1) in rat and rabbit liver microsomes. Cancer Res. 48:5837-5890. Jones, A.W. 2000. Elimination half-life of acetone in humans: Case reports and review of the literature. J. Anal. Toxicol. 24(1):8-10.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Koop, D.R., A. Chernosky, and E.P. Brass. 1991. Identification and induction of cytochrome P450 2E1 in rat Kupffer cells. J. Pharmacol. Exp. Ther. 258(3):1072-1076. Krasavage, W.J. , J.L. O'Donoghue, and G.D. DiVincenzo. 1982. Ketones. Pp. 4709-4727 in Patty's Industrial Hygiene and Toxicology, 3rd Rev. Ed. G.D.Clayton, and F.E.Clayton, eds. New York: John Wiley & Sons. Lee, C., K.C. Watt, A.-M. Chan, C.G. Plopper, A.R. Buckpitt, and K.E. Pinkerton. 1998. Site-selective differences in cytochrome P450 isoform activities. Drug. Metab. Dispos. 26(5):396-400. Liebich, H.M., W. Bertsch, A. Zlatkis, and H.J. Schneider. 1975. Volatile organic components in the Skylab 4 spacecraft atmosphere. Aviat. Space Envir. Med. 46(8):1002-1007. Liu, J., C. Sato, and F. Marumo. 1991. Characterization of the acetominophenglutathione conjugation reaction by liver microsomes: Species difference in the effects of acetone. Toxicol. Lett. 56:269-274. Lo, H.H., V.J. Teets, D.J. Yang, P.I. Brown, and G.O. Rankin. 1987. Acetone effects on N-(3,5-dichlorophenyl)succinamide-induced nephrotoxicity. Toxicol. Lett. 38:161-168. Löf, A., M. Nordqvist, and E. Wigaeus. 1980. Inhalation exposure of mice to acetone. Toxicol. Lett. Special Issue 1:213. Lorr, N.A., K.W. Miller, H.R. Chung, and C.S. Yang. 1984. Potentiation of the hepatotoxicity of N-nitrosodimethylamine by fasting, diabetes, acetone, and isopropanol. Toxicol. Appl. Pharmacol. 73(3):423-431. Mast, T.J., R.L. Rommereim, R.J. Weigel, R.B. Westerberg, B.A. Schwetz, and R.E. Morrissey. 1989. Developmental toxicity study of acetone in mice and rats. Teratology 39(5):468. Matsushita, T., E. Goshima, H. Miyagaki, K. Maeda, Y. Takeuchi, and T. Inoue. 1969. Experimental studies for determining the maximum permissible concentration of acetone-2. Biological reaction in the six-day exposure to acetone. Sangyo Igaka (Jpn. J. Ind. Health) 11:507-511. Mikalsen, A., J. Alexander, R.A. Anderson, and M. Ingelman-Sundberg. 1991. Effect of in vivo chromate, acetone and combined treatment on rat liver in vitro microsomal chromium (VI) reductive activity and on cytochrome P450 expression. Pharmacol. Toxicol. 68:456-463. Mirchev, N. 1977. Hepatorenal lesions after acute acetone intoxication. Vutr. Boles. 17:89-92. Moldeus, P., and V. Gergely. 1980. Effect of acetone on the activation of acetaminophen. Toxicol. Appl. Pharmacol. 53:8-13. Nelson, D.L., and B.P. Webb. 1978. Acetone. Pp. 179-191 in Kirk-Othmer Encyclopedia of Chemical Toxicology, 3rd Ed. New York: John Wiley & Sons. NTP (National Toxicology Program). 1991. Toxicity studies of acetone (CAS No. 67-64-1) in F344/N rats and B6C3F1 mice (drinking water studies). NTP TOX3, NIH Publication No. 91-3122. NTP, Research Triangle Park, NC.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 OSHA (Occupational Safety and Health Administration). 1989. Acetone [online]. Available: www.cdc.gov/niosh/pel88/67-64.html [accessed Jan. 25, 2005]. Ramu, A., J. Rosenbaum, and T. Blaschke. 1978. Disposition of acetone following acute acetone intoxication. West. J. Med. 129(5):429-432. Ronis, M.J.J., J. Huang, V. Longo, N. Tindberg, M. Ingelman-Sundberg, and T.M. Badger. 1998. Expression and distribution of cytochrome P450 enzymes in male rat kidney: Effects of ethanol, acetone and dietary condition—assay and product identification by thin layer chromatography. Biochem. Pharmacol. 55(2):123-129. Ross, D.S. 1973. Acute acetone intoxication involving eight male workers. Ann. Occup. Hyg. 16:73-75. Rowe, V.K., and M.A. Wolf. 1963. Ketones. Pp. 1719-1731 in Patty's Industrial Hygiene and Toxicology, 2nd Rev. Ed. G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Sakata, M., J. Kikuchi, and M. Haga. 1989. Disposition of acetone, methyl ethyl ketone and cyclohexanone in acute poisoning. Clin. Toxicol. 12(1-2):67-77. Sipes, I.G., M.L. Slocumb, and G. Holtzman. 1978. Stimulation of microsomal dimethylnitrosamine-N-demethylase by pretreatment of mice with acetone. Chem. Biol. Interact. 21:155-166. Stewart, R.D., C.L. Hake, A. Wu, S.A. Graff, H.V. Forster, W.H. Keeler, A.J. Lebrun, P.E. Newton, and R.J. Soto. 1975. Acetone: Development of a biologic standard for the industrial worker by breath analysis. Cincinnati, OH: National Institute for Occupational Safety and Health. Tindberg, N., and M. Ingelman-Sundberg. 1989. Cytochrome P-450 and oxygen toxicity.Oxygen-dependent induction of ethanol-inducible cytochrome P-450 (IIE1) in rat liver and lung. Biochemistry 28:4499-4504. Wang, G., G. Maranelli, L. Perbellini, E. Raineri, and F. Brugnone. 1994. Blood acetone concentration in "normal people" and in exposed workers 16 h after the end of the workshift. Int. Arch. Occup. Environ. Health 65:285-289. Widmark, E. 1919. Studies in the concentration of indifferent narcotics in blood and tissues. Acta Med Scand. 52:87-164. Wigaeus, E., S. Holm, and I. Estrand. 1981. Exposure to acetone. Uptake and elimination in man. Scand J. Work Environ. Health 7:84-94. Wigaeus, E., A. Löf, and M. Nordqvist. 1982. Distribution and elimination of 2-[14C]-acetone in mice after inhalation exposure. Scand. J. Work Environ. Health 8(2):121-128. Windholz, M. 1983. Acetone. P. 2 in Merck Index, 9th Ed. M. Windholz, and N.J. Rahway, eds. Rahway, New Jersey: Merck & Co. Yoo, J.S.H., H. Ishizaki, and C.S. Yang. 1990. Roles of cytochrome-P450IIE1 in the dealkylation and denitrosation of N-nitrosodiethylamine in rat liver microsomes. Carcinogenesis 7:2239-2243.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Zettinig, G., N. Watzinger, B. Eber, G. Henning, and W. Klein. 1997. Survival after poisoning due to intake of ten-times lethal dose of acetone [in German]. Dtsch. Med. Wochenschr. 122(48):1489-1492.