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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"3 Ethylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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3 Ethylene Glycol John T. James, Ph.D., DABT Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Ethylene glycol (EG) (see Table 3-1) is a colorless, odorless, slightly vis- cous, hygroscopic liquid with a bittersweet taste (Cavender and Sowinski 1994). TABLE 3-1 Physical and Chemical Properties of Ethylene Glycol Formula HO-CH2-CH2-OH CAS registry no. 107-21-1 Synonyms 1,2-ethanediol, 1,2-dihydroxyethane, ethane-1,2-diol, ethylene alcohol, ethylene dehydrate Molecular weight 62.07 Boiling point 197.4oC Melting point –13.4oC Specific gravity 1.11 (at 25oC) Solubility Soluble in water and aliphatic alcohols, almost insoluble in Hydrocarbons OCCURRENCE AND USE EG has many uses. It is used as antifreeze in motor vehicles and in hy- draulic fluids, heat-exchange fluids, inks, solvents, softening agents, and the synthesis of many useful chemicals. It was used in heat-exchange loops in early U.S. space capsules and was present in heat-exchange loops in the Russian Mir space station. Leakage of EG from coolant loops in Mir was a persistent prob- lem during the past few years because the space station was used beyond its intended service life. Once EG escapes from a coolant loop into the atmosphere, 86

Ethylene Glycol 87 it is removed into the humidity condensate or recondenses on cool surfaces only to revolatilize later when the surface warms up. Estimates made with detector tubes showed airborne concentrations up to 75 milligrams per cubic meter (mg/m3) in the Mir space station, and ground-based analyses of water samples from Mir showed concentrations up to 440 mg/liter (L) in the humidity conden- sate and 46 mg/L in the recycled water (Lizanna Pierre, Wyle Laboratories, per- sonal commun., 1999). Even though EG is not used in coolant loops in the In- ternational Space Station, it has been found in the U.S. laboratory humidity condensate at concentrations up to 11 mg/L; however, it has not been detected in the potable water (John R. Schultz, Wyle Laboratories, unpublished report, January 9, 2002). PHARMACOKINETICS AND METABOLISM The behavior of EG after it has been ingested into the body has been gen- erally understood for many years, but new discoveries have been reported in the past few years. The understanding of the behavior of EG has important implica- tions for treating acute poisonings and for understanding the metabolic path- ways that lead to detoxification or to production of more toxic metabolites. There are likely to be significant interindividual differences in the metabolism of EG because of genetic variations in the catalytic activity of key enzymes in the major metabolic pathway. Absorption Fasted rats given gavage doses of EG at 6 or 9 milliliters per kilogram (mL/kg) of body weight rapidly absorbed it into the body, where it reached peak blood concentrations in 1 to 4 h (Winek et al. 1978). At lower gavage doses of about 1 g/kg, serum concentrations of EG peaked in fasted rats and dogs 2 h after the dose was administered (Hewlett et al. 1989). Likewise, at an oral dose of 0.9 g/kg, female monkeys had peak plasma concentrations of EG of about 120 milligrams per deciliter (mg/dL) 2 h after dosing (McChesney et al. 1971). Rats and mice exposed orally at up to 1,000 mg/kg rapidly and completely ab- sorbed the dose (Frantz et al. 1996). Distribution Evidence from clinical cases of EG poisoning suggests that its volume of distribution is about 0.5 L/kg (Jacobsen et al. 1988), which indicates distribution into the total body water. The tissue distribution of 14C from [1,2- 14C]EG given orally was similar in female Sprague-Dawley rats and in CD-1 mice when the

88 Spacecraft Water Exposure Guidelines same doses were given (Frantz et al. 1996). The species were tested at doses ranging from 10 to 1,000 mg/kg and tissues were assayed 96 h after dosing. In major organs from both species, the largest portion of the dose was found in the liver, followed by the kidney, lung, and brain. In terms of label found per gram of tissue, the largest amount was in the liver, followed by the lung and kidney, which were similar; the smallest amount of labeling was found in the brain. In another study, after an intravenous dose of [14C]EG (139 mg/kg) to monkeys, 15% was excreted in the urine by 4 h, but the remainder of the dose (label) was uniformly distributed to body tissues (McChesney et al. 1971). Metabolism Many investigators have studied EG metabolism in an effort to understand how its ingestion causes the range of toxic symptoms and metabolic distur- bances. The metabolism has been summarized as shown in Figure 3-1 (ATSDR 1997). EG is oxidized by alcohol dehydrogenase to glycoaldehyde, which is oxi- dized by aldehyde oxidase or aldehyde dehydrogenase to glycolic acid and gly- oxal. Lactate dehydrogenase appears to be involved in converting glyoxal to glycolic acid, glycolic acid to glyoxylic acid, and glyoxylic acid to oxalic acid, which is further oxidized to formic acid and carbon dioxide by a process involv- ing coenzyme A and flavin mononucleotides. Glyoxylic acid is metabolized to a number of other products, which have no apparent bearing on the toxicity of EG. The liver and kidney are believed to be the major sites where EG is metabo- lized. Alcohol dehydrogenase is a dimer with multiple molecular forms deter- mined by at least five gene loci (Agarwal and Goedde 1992). Certain subunits have a 20-fold higher metabolic capacity than others, so it is reasonable to ex- pect considerable interindividual variability in the metabolism of EG. Likewise, aldehyde dehydrogenase has a number of different molecular forms with differ- ent catalytic capabilities (Thomasson et al. 1993), which could further contrib- ute to interindividual variation in susceptibility to high oral doses of EG. Genetic polymorphisms in the human population can affect the suscepti- bility of individuals to xenobiotics such as EG when those polymorphisms con- trol the enzymatic capabilities of creating or eliminating toxic metabolites. The allelic variants of aldehyde dehydrogenase 2 (ALDH2) produce enzymes that have a wide range in their ability to catalyze the conversion of small aldehydes to organic acids. The nonfunctional allele is rare in most populations, but about 40% of Asians are heterozygous and 5% are homozygous for this allele. Be- cause astronauts are not screened for this genetic factor, one must assume that some individual astronauts are homozygous for the nonfunctional allele. De- pending on the mechanism of EG toxicity, they may be more or less susceptible to the toxic effects because of the accumulation of glycoaldehyde and reduced production of a downstream metabolite.

Ethylene Glycol 89 Free radical metabolites of EG have been found in bile and urine from male Sprague-Dawley rats given [13C2]EG (Kadiiska and Mason 2000). The free radical metabolites were demonstrated by the formation of adducts of an EG metabolite and a trapping agent, α-(4-pyridyl-1-oxide)-N-tert-butylnitrone. The formation of these adducts increased when 4-methylpyrazole, an alcohol dehy- drogenase inhibitor, was given concurrently with the EG dose, which suggests that more substrate is available for the free radical reaction when the primary metabolic pathway is blocked. Because blocking the major pathway also re- duces the toxicity of EG, the authors suggested that the free radicals do not con- tribute significantly to the acute toxicity of EG. There is an alternative interpretation of the above 4-methylpyrazole data that Kadiiska and Mason (2000) did not consider. Hepatic CYP2E1 can catalyze the conversion of EG to formaldehyde. Because the reaction proceeds through FIGURE 3-1 Metabolic pathways showing oxidation of EG. Source: ATSDR 1997.

90 Spacecraft Water Exposure Guidelines the formation of H2O2 (Kukielka and Cederbaum 1995), it likely involves the formation of a reactive species and an EG radical intermediate. Thus, the protec- tive effect of 4-methylpyrazole on EG toxicity may also be the result of CYP2E1 inhibition and reduced EG radical formation, rather than inhibition of alcohol dehydrogenase. It has been recognized for some time that clinical management of EG poi- soning can be improved by measuring glycolic acid rather than EG in body flu- ids, especially if the ingestion occurred more than 24 h before hospital admis- sion (Fraser et al. 2002). Use of 4-methylpyrazole to block the activity of alcohol dehydrogenase in converting EG to more toxic metabolites has been recently recommended. For example, 10 patients treated with this antidote and having an initial blood concentration of less than 10 millimoles of glycolic acid per L did not develop renal symptoms (Fraser et al. 2002). The mechanism of EG-induced renal toxicity is not well understood at the cellular level. In vitro evidence from a study of human proximal tubule (HPT) cell death indicates that glycolic acid may not be the proximate metabolite caus- ing renal effects. Even though this metabolite is present at higher concentrations in the blood than oxalic acid, it appears to be the latter that causes the renal cell damage (McMartin and Cenac 2000). Dead and live cells were distinguished by the entry or exclusion of fluorescent dyes into the cultured cells. Oxalate pro- duced a concentration- and time-dependent entry of the red fluorescent dye into the cells with damaged membranes. Glycolic acid and glyoxylic acids failed to produce similar effects on the HPT cells at concentrations associated with renal effects in humans poisoned with EG. The authors concluded that oxalate (oxalic acid) in concentrations similar to urinary concentrations in EG-poisoned patients produces cytotoxicity in cultured HPT cells (McMartin and Cenac 2000). Another in vitro study of cell toxicity reached a different conclusion. Mouse proximal tubular segments (PTS) were incubated with EG or one of its metabolites (glycolate, glycoaldehyde, glyoxalate, or oxalate) for 15 to 60 min- utes (Poldelski et al. 2001). Cell injury was assessed by lactate dehydrogenase release, ATP depletion, or depletion of phospholipids in cell membranes. EG, glycolate, and oxalate did not produce overt injury to cells in the PTS. The au- thors concluded that glycoaldehyde and glyoxylate, because they produced pro- found ATP depletion and lactate dehydrogenase release in the PTS, are the pri- mary metabolites responsible for EG nephrotoxicity. One must simply conclude that there is no consensus on which EG me- tabolite is responsible for the toxic effects on the kidney. Metabolites and devel- opmental toxicity are discussed further in the developmental toxicity section. Elimination The half-life of EG in the blood depends on dose, route of administration, species, and strain. The estimated half-life in humans has been reported to be

Ethylene Glycol 91 3 to 6 h (Winek 1975, Peterson et al. 1981); however, in an untreated patient with renal failure the half-life for elimination from plasma was 8.4 h (Jacobsen et al. 1988). Hemodialysis of this patient 11 h after admission reduced the half- life in plasma to 3 h; conversely, later treatment with intravenous ethanol pro- longed the elimination of EG from the blood. In Sprague-Dawley rats given near-lethal doses (6 or 9 mL/kg) the half- life in blood was estimated to be 5 to 7 h, with the longer half-life associated with the lower dose (Winek et al. 1978). At less toxic doses, the elimination half-life seems to be somewhat shorter. In rats given EG at 2 g/kg, the half-life was only 1.7 h, whereas in dogs given EG at 1 to 1.4 g/kg, the half-life was 3.4 h (Hewlett et al. 1989). In CD-1 mice given [14C]EG at 0.01 to 1 g/kg, the amount of label eliminated in the breath and urine combined was 75% to 90% of the dose; however, at the lowest dose, 55% was eliminated in the breath and at the highest dose 56% was eliminated in the urine (Frantz et al. 1996). The route of elimination was dose dependent in F344 rats given an intravenous injection of EG. At 20 and 200 mg/kg, 39% of the dose was exhaled as CO2 and 2% was excreted by the kidney as glycolate; however, at 1,000 and 2,000 mg/kg, 26% of the dose was eliminated as CO2 from the respiratory system and 20% was ex- creted as glycolate in the urine (Marshall 1982). The renal toxicity occurs as the detoxification pathways are overwhelmed and more toxic metabolites are elimi- nated by the kidney rather than by exhalation of less toxic CO2. TOXICITY SUMMARY The toxicity of EG is well understood from fatal and near-fatal acute poi- sonings in humans as well as long-term studies in animals consuming EG in their water or food. There are three or four recognized stages in acute human poisonings. The long-term effects of EG ingestion in animals include adverse effects on the kidney, blood cells, and possibly the liver. There is some evidence that EG can cause reproductive and developmental toxicity in animals. Reviews of EG toxicity have been published (LaKind et al. 1999, Brukner and Warren 2001). Acute Toxicity (1- to 5-d Exposure) Stages of EG Poisoning Oral ingestion is by far the major route of exposure of humans to EG. In the United States, 6 to 60 deaths per year are attributed to ingestion of EG (ACGIH 1996). Life-threatening poisonings can occur as a result of deliberate or accidental ingestion of about 1.4 mL/kg (about 100 mL for a 70-kg person) (ATSDR 1997). On the basis of milligram per kilogram of body weight, humans

92 Spacecraft Water Exposure Guidelines seem to be more susceptible than laboratory animals to the toxicity of orally ingested EG (ACGIH 1996, Table 3-2). Ingestion of a single large dose of EG leads to a three- to four-stage se- quence of clinical symptoms beginning with the central nervous system (CNS) (Cavender and Sowinski 1994). This stage typically begins soon after ingestion and can last up to 12 h. The symptoms resemble drunkenness and they can pro- gress to coma, convulsions, and death if the dose is large enough. These CNS effects are thought to be due primarily to unmetabolized EG or its aldehyde me- tabolites (Parry and Wallach 1974). The second stage lasts from 12 to 36 h after ingestion and involves car- diopulmonary effects. Clinical findings can include tachypnea, tachycardia, hy- potension, cyanosis, pulmonary edema, bronchopneumonia, and congestive heart failure. This stage is believed to be caused by metabolic acidosis (glycolic acid and lactic acid) and by hypocalcemia due to chelation of calcium with ox- alate to form insoluble crystals. If a person survives the initial stages, then a third stage involving renal failure may ensue. The renal injury may be reflected in a urinalysis by the pres- ence of protein, red and white blood cells (RBC and WBC), casts, and calcium oxalate crystals. Blood urea nitrogen (BUN) and creatinine may be elevated and the end result can be tubular necrosis, anuria, and death. The formation of cal- cium oxalate in the kidney plays a major role in this stage; however, there is also evidence that products of EG metabolism lead directly to tubular necrosis. According to some investigators, a fourth “cerebral stage” involving neu- rologic symptoms can appear approximately 2 wk after ingestion of EG (Chung and Tuso 1989). Cranial nerve dysfunction, facial paralysis, hearing loss, and optic nerve damage can be found at this time. These late symptoms are thought to be due to accumulated metabolites of EG that produce metabolic acidosis. Acute Toxicity Data The acute toxicity database consists almost entirely of lethality studies in animals and lethal, or near-lethal, ingestions in humans (see Table 3-2). These data, which involve a broad range of species, suggest that there is not more than a 6-fold interspecies variation in the amount (based on gram per kilogram of body weight) of EG required to cause death. Humans seem to be one of the more susceptible species; however, the conditions of human exposure differed greatly from the conditions used to expose animals. The circumstances surrounding the incidents of human ingestion of EG are important to understanding how to use these “data.” Walton (1978) reported details of six fatal EG poisonings from deliberate ingestion of antifreeze, with the intention of suicide. The suicide attempts followed publicity surrounding an

TABLE 3-2 Summary of Toxic Effects Dose or Route or Concentration Exposure Species Effects Reference Acute Dosages (1-5 d) 8-15 g/kg Oral Mouse LD50. Cavender and Sowinski 1994 4-13 g/kg Oral Rat LD50. Cavender and Sowinski 1994, NTP 1993 7-11 g/kg Oral Guinea pig LD50. Cavender and Sowinski 1994 5 g/kg Oral Rabbit LD50. Cavender and Sowinski 1994 2-3 g/kg Oral Human, n=2 Lower lethal. Walton 1978 1.6 g/kg Oral Human Minimum lethal estimate.a Gessner et al. 1961 1.1 g/kg Oral Human, n=7 Minimum lethal estimate. Hunt 1932, as cited in Laug et al. 1939 1.1 g/kg over 3 d Oral Human, n=5 Serious, but not lethal. Moriarty and McDonald 1974 0.05-0.25 g/kg/d Oral B6C3F1 mouse, Bone marrow hypocellularity, suppression of progenitor colony Hong et al. 1988 for 4 d gavage M/F formation, and erythropoiesis. All reversible in females. (Continued) 93

94 TABLE 3-2 Continued Dose or Route or Concentration Exposure Species Effects Reference Short-term Dosages (6-30 d) 0.25% 28 d DW Charles River rat, Renal lesions (weanlings). Gershoff and M, n=6 Andrus 1962 0.5%-4.0% 10 d DW SD rat, F, n=10 Increased incidence or severity of renal lesions, decreased RBC Robinson et al. indices and WBC count in 4% group NOAEL was 2%.a 1990 0.5%-4.0% 10 d DW SD rat, M, n =10 Increased incidence or severity of renal lesions at 2% and 4%; Robinson et al. NOAEL was 0.5%.a 1990 1.0% 21 d DW Porton rat, M Oxalate deposits in kidney. Rofe et al. 1986 0.25%-10% 6-13 d DW Macaque, n=2-7 Renal lesions, azotemia; no renal crystals at 0.25%. Roberts and Seibold 1969 Subchronic Dosages (31-180 d) 0.25%-10% 13-157 d Macaque, M, Anemia, azotemia. Roberts and DW n=2-7 Seibold 1969 0.25%-2% 90 d DW SD rat, M, n=10 2/10 died at high dose; renal lesions increased in severity or Robinson et al. incidence at all concentrations; LOAEL was 0.25%.a 1990 0.5%-4% 90 d DW SD rat, F, n=10 8/10 died at highest dose; renal lesions increased in severity Robinson et al. or incidence in 2% and 4% groups; decreased leukocytes in 1990 all groups except 1% group, which was taken as the NOAEL.a 1% 70 d DW Rat, M, n=5-13 Death due to renal failure, liver had centrilobular necrosis. Hanzlik et al. 1947 0.3%-5% 94 d feed B6C3F1 mouse, No clinical signs, no changes in clinical pathology values, Melnick 1984 M, n=10 nephrosis, and centrilobular degeneration in liver of 2.5% and NTP 1993 5% groups. NOAEL was 1.25% (3 g/kg/d)a for these effects.

0.3%-5% 94 d feed B6C3F1 mouse, F, NOAEL for all effects. Melnick 1984 n=10 NTP 1993 0.32%-5.0% 91 d feed F344 rat, M, n=10 1.25% NOAEL, 2.5% and 5.0% showed increased BUN, Melnick 1984 creatinine, and renal crystals. 0.32%-5.0% 91 d feed F344 rat, F, n=10 5.0% nephrosis, NOAEL other effects. Melnick 1984 Chronic Dosages (0.5-3 y) 0.2% 3 y feed Rhesus monkey, NOAEL for histopathology (2/2) of many organs including Blood et al. 1962 M, n=2 kidney. 0.5% 3 y feed Rhesus monkey, NOAEL for histopathology (1/1) of many organs including Blood et al. 1962 F, n=1 kidney. 0.2% 2 y feed SD rat, M, n=16 NOAEL for renal calcification, effects seen at 0.5%, 1%, and 4%. Blood 1965 Increased mortality in 1% and 4% groups. Normal hematology. 0.5% 2 y feed SD rat, F, n=16 NOAEL for renal calcification, effects seen at 1% and 4%. Blood 1965 Increased mortality in 4% group. Normal hematology. 1%-2% 2 y feed Albino rat, M/F, Renal oxalate crystals, atrophy, fibrosis. Liver centrilobular atro- Morris et al.1942 n =10 phy, bile duct proliferation, fatty changes, bladder stone in males. 0.04-1.0 g/kg/d 2 y feed F344 rat, F n=130 NOAEL 0.2 g/kg/da for mild fatty metamorphosis, monocyte DePass et al. infiltrate, and granulomas in liver; 1.0 g/kg/d was NOAEL for all 1986a other effects including neoplasia. 0.04-1.0 g/kg/d 2 y feed F344 rat, M, NOAEL 0.2 g/kg/da renal injury (creatinine, BUN, lesions) DePass et al. n=130 mineralization of heart, lung stomach, and for parathyroid 1986a hyperplasia. 80% of 1% group were dead by 15 months. Blood changes at 12-month sacrifice in 1.0% group: RBC, hematocrit, hemoglobin decreased 15%. WBC count increased 60%. NOAEL = 0.2 g/kg/d.a (Continued) 95

96 TABLE 3-2 Continued Dose or Route or Concentration Exposure Species Effects Reference 1.0 g/kg/d 2 y feed CD1 mouse, M/F, NOAEL for clinical signs, histopathology, and neoplasia. DePass et al. n=80 1986a 0.62%-2.5% 2 y feed B6C3F1 mouse, NOAEL for clinical pathology in all groups. 1.5 g/kg/d NOAEL NTP 1993 (1.5-6 g/kg/d) M, n=50 for liver hyaline degeneration. NOAEL for neoplasms in all groups. Nephropathy in high-dose group at 15-month interim sacrifice. 1.25%-5% 2 y feed B6C3F1 mouse, NOAEL for clinical pathology in all groups 1.25%. LOAEL lung NTP 1993 (3-12 g/kg/d) F, n=50 arterial medial hyperplasia (10/50 versus 3/50 in controls). 1.25% NOAEL for liver hyaline degeneration. NOAEL for neoplasms in all groups. a Result was used as a basis for acceptable concentrations for the toxic effect described (see Table 3-9). Abbreviations: DW, drinking water; F, female; LD50, 50% lethal dose; M, male; SD, Sprague-Dawley.

Ethylene Glycol 97 incident in which 11 garage workers mistakenly ingested antifreeze, thinking it was cherry brandy. The lowest estimated lethal ingestion was 150 mL in two of the victims, who survived for 36 and 72 h after drinking the antifreeze. If we assume a body weight of 70 kg, the amount of EG these persons ingested was 2.4 g/kg. No information was provided on the amount ingested by persons who survived. An older report by Laug et al. (1939) cited an estimate by Hunt (1932) that experience with seven fatal EG poisonings suggests that approximately 100 mL (roughly 1.6 g/kg) is the minimum fatal amount. Gessner et al (1961) pro- vided an estimate, without specific supporting data, of 1.6 g/kg as the minimum lethal amount. Moriarty and McDonald (1974) reported on 12 cases of persons aged 12 to 17 who ingested antifreeze over a 3-d period. The amount ingested by the two most serious cases was not available; however, data on those ingest- ing the intermediate amount are useful. Five people ingested 90 to 200 mL (av- erage 150 mL) and most were seriously ill but survived. If one assumes a body weight of 50 kg and that the EG was ingested at a rate of 50 mL/d for 3 d, then the daily dose was 1.1 g/kg. Although certain assumptions were required to in- terpret the various case studies, there is a fairly consistent picture of the amount of EG needed to elicit a fatal response in humans (Table 3-2). One exception to the case reports involving near-lethal concentrations is that of Hong et al. (1988) in which male and female mice were given gavage doses on 4 consecutive days at 0, 0.05, 0.1, or 0.25 g/kg. Various bone marrow cellular end points were examined in 5 to 10 mice per group 1, 5, and 14 d after the final dose. On postexposure days 1 and 5, bone marrow cellularity was de- pressed approximately 20% in the high-dose mice (male and female); the de- pression was reversible by 14 d in the females, but not in the males, where the middle dose group showed a 20% depression at 14 d. Up to a 40% depression in colony-forming ability of granulocyte/macrophage progenitors was seen in both sexes at the two highest doses but was reversed in females by 14 d. Even though the colony-forming ability of the progenitors was not significantly depressed 1 and 5 d after dosing in males in the low-dose group, it was depressed approxi- mately 20% in male mice held for 14 d after dosing. Erythropoiesis, as meas- ured by 59Fe incorporation and counting of erythroid precursors in culture, was unaffected in females and in males receiving the two lowest doses, but there was a 40% reduction in 59Fe incorporation in high-dose males. A battery of hema- tologic assessments and histopathology examinations (lung, heart, liver, kidney, stomach, urinary bladder, intestine, thymus, spleen, and gonads) revealed no changes in circulating blood cells or tissues (Hong et al. 1988). Short-Term Toxicity (6- to 30-d Exposure) Renal Toxicity A number of studies in rodents and in primates have shown that short- term, oral administration of EG is toxic to the kidney (see Table 3-2). Gershoff

98 Spacecraft Water Exposure Guidelines and Andrus (1962) assessed the effect of vitamin B6 and magnesium on the calcium oxalate deposition in weanling male Charles-River rats (six per group) given drinking water containing 0.25% EG and fed a synthetic diet supple- mented with large or small amounts of vitamin B6 or magnesium. There were no renal effects in rats given the high magnesium supplement, and in those given the high vitamin B6 supplement renal lesions were reduced in severity compared with rats given reduced supplements. The results of this study are difficult to apply to risk assessment because of the young age of the rats, the lack of unexposed controls, and the unusual diets used. Another study with findings that are difficult to apply to risk assessment is that reported by Roberts and Seibold (1969) on macaques. The purpose of their study was to induce oxalate stones in the urinary tract of the animals, and their primary finding was evidence of renal injury in the absence of renal crystals, which were present in most of the monkeys given 15 mL/kg (n = 7) or more over 6 to 13 d. After 6 to 13 days of exposure to EG, the three monkeys given less than 15 mL/kg had one kidney removed and two of the three animals had a blood urea nitrogen (BUN) measurement done (two animals from the higher- dose groups also had BUN measured). These measurements suggested some degree of azotemia (nitrogen retention from something other than primary renal disease) in the low-dose animals (no controls were reported), and there was a “slight amount of protein precipitate in Bowman’s spaces” found during the histopathology examination of the kidney that was removed. It was not clear why BUN measurements were reported for only 4 of the 10 monkeys. Even though the study was done on primates, the small number of subjects and the lack of controls make it difficult to apply the results to human risk assessment. Renal lesions have been reported in Sprague-Dawley rats given EG in their drinking water for 10 d (Robinson et al. 1990). Male and female rats, in groups of 10 animals, were given 0%, 0.5%, 1.0%, 2.0%, and 4.0% EG in their water. At sacrifice, tissues were collected for histopathology and blood was taken for a clinical pathology study. Inflammation and tubular necrosis were increased in incidence or severity in males of the 2.0% and 4.0% groups and less severe changes (tubular dilatation and proteinaceous material) were noted in some of the females receiving 4% doses. Clinical chemistry values were “vari- able” but appeared to show an increase in BUN and possibly creatinine in the highest-dose males. The highest no-observed-adverse-effect level (NOAEL) for kidney effects in male rats was 0.5% based on the committee’s recommendation. Decreased RBC and WBC Counts There is some evidence that short-term exposures can affect RBC and WBC parameters in rodents. Female, but not male, rats consuming 4.0% EG in their drinking water for 10 d showed a 7% to 10% decrease in RBC indices and a 30% decrease in WBC count (Robinson et al. 1990). Given the degree of vari-

Ethylene Glycol 99 ability in the clinical pathology measurements, one cannot be certain that this change is due to EG consumption rather than a spurious finding. Subchronic Toxicity (31 to 180 d) Renal Effects Subchronic ingestion of EG causes renal injury in rodents, with males more susceptible than females and rats more susceptible than mice (Table 3-2). At least three strains of rat and one strain of mouse have been studied. In an early study, using what would now be considered an unconventional design, Hanzlick et al. (1947) found that rats and mice (strains unspecified) were sus- ceptible to renal injury from EG in drinking water, and this injury appeared to be the cause of death. In a more recent drinking water study of 90 d duration, Robinson et al. (1990) used Fischer’s exact test to determine that the dose show- ing no difference from controls in the incidence of renal lesions in Sprague- Dawley rats was 0.5% in males and 1.0% in females. These values were taken as statistically demonstrated NOAELs. Decreased WBC Counts Robinson et al. (1990) reported that WBC counts decreased significantly in all but one exposed group of female Sprague-Dawley rats but not in any dose groups of male rats. The reported values were 5,000 WBC/dL for controls and 3,400, 3,500, and 2,500 WBC/dL for the 0.5%, 2.0%, and 4.0% groups, respec- tively. Presumably, the 1.0% group was not significantly different from con- trols. According to the abstract of the study, 8 of 10 female rats in the highest- dose group died before sacrifice, so the significance of a decrease in WBC counts is questionable. One can conclude that EG may have depressed the WBC count at the highest dose but only in association with making the rats terminally ill for other reasons. Liver Injury Although EG is considered primarily a renal toxicant, there is evidence that liver damage can occur at subchronic dosages comparable to those that in- duce renal injury. Although death in rats given EG in their drinking water was believed to be due to renal failure, Hanzlik et al. (1947) noted that many of the rat livers showed centrilobular necrosis. Centrilobular degeneration was also reported in male B6C3F1 mice given 2.5% or 5% EG in their food for 13 wk (Melnick 1984, NTP 1993). Female rodents seem to be more resistant to both renal injury and liver injury.

100 Spacecraft Water Exposure Guidelines Chronic Toxicity (0.5 to 3 y) Renal Toxicity Chronic ingestion of EG in feed has been shown to induce renal injury in rodents but not in macaques (Table 3-2); chronic studies using drinking water as the source of EG exposure were not found. The negative findings in the chronic monkey feeding study may seem to conflict with the positive findings reported for subchronic exposure of macaques by drinking water (Roberts and Seibold 1969); however, the feeding doses represent lower doses than the drinking water doses. The renal toxicity from chronic ingestion of EG was demonstrated as early as the 1930s and later studies have served primarily to refine the early ob- servations (Morris et al. 1942, Blood 1965). Chronic studies in Sprague-Dawley rats and F344 rats show that male rats are more susceptible than female rats to renal injury (Blood 1965, DePass et al. 1986a). The study by DePass et al. (1986a) was considered the best study on rats because of the large number of animals used in each group, the standard design of the exposure protocol, and the wide range of toxicity end points evaluated. The NOAEL for renal effects was 0.2 g/kg/d in males and 1.0 g/kg/d in females (DePass et al. 1986a). Two chronic studies in mice have not demonstrated renal injury at concentrations up to 6 g/kg/d in males and 12 g/kg/d in females (De- Pass et al. 1986a, NTP 1993). Liver Injury Although EG is not generally considered a hepatotoxicant, liver effects of- ten can be demonstrated in rodents at concentrations that induce renal effects and sometimes below concentrations that induce renal injury. For example, fe- male F344 rats did not show renal effects in a 2-y feeding study at any dose; however, the high-dose animals showed fatty metamorphosis, monocyte infiltra- tion, and granulomas in liver sections (DePass et al. 1986a). The NOAEL for liver injury in female rats was 0.2 g/kg/d. Likewise, male and female B6C3F1 mice did not show renal injury in a chronic feeding study; however, hyaline degeneration of the liver was seen in both sexes (NTP 1993). The NOAEL for liver effects was 1.5 g/kg/d in male mice and 3 g/kg/d in female mice. Lung Effects Lung arterial medial hyperplasia was reported in female mice in all expo- sure groups in a chronic feeding study (NTP 1993). At the 2-y end point the incidences of this change were as follows: controls (3 of 50), 3 g/kg/d (10 of 50), 6 g/kg/d (10 of 51), and 12 g/kg/d (23 of 50). There was not an increase in severity of the change, which was minimal to mild for each dose group (NTP

Ethylene Glycol 101 1993). Changes of this sort were not reported in male mice or in any other spe- cies. The National Research Council committee advised that the report of lung arterial medial hyperplasia is an unusual outcome related to the nature of the study rather than an adverse effect of EG ingestion. Hematotoxicity At the 12-month sacrifice of male rats DePass et al. (1986a) found a 15% depression in RBC indices and a 60% increase in WBC count in the 1.0-g/kg/d dose group. Because more than 20% of the males in this group died before the 12-month sacrifice, the changes may not reflect specific toxic action by EG; on the other hand, EG could be directly interfering with erythropoietin production by the kidney. Soft Tissue Mineralization DePass et al. (1986a) reported mineralization of many different organs in the male rats given EG at 1.0 g/kg/d for several months (deaths occurred 9 to 17 months into the study). Mineralization was observed in heart muscles and ves- sels and in the lung interstitium, stomach, and other vasculature. The authors suggested that it was partly due to the loss of calcium (with oxalate), compensa- tory parathyroid hyperplasia with increased parathyroid hormone secretion, and calcium resorption. Parathyroid hyperplasia was observed in the high-dose male rats. Genotoxicity A variety of in vitro tests of genotoxicity have consistently produced negative results for EG (NTP 1993). No mutagenic activity was found in four strains of Salmonella typhimurium treated at concentrations up to 10 mg of EG per plate, with and without the S9 fraction from the liver of arochlor-treated rats and hamsters. Likewise, EG was negative in the mouse lymphoma assay at con- centrations up to 5 mg/mL, with and without the S9 fraction from livers of treated rats. EG did not induce chromosomal aberrations or sister chromatid exchanges in Chinese hamster ovary cells either with or without the S9 fraction from the livers of treated rats (NTP 1993). Dominant lethal mutations were not found in F344 rats fed doses up to 1.0 g/kg/d for approximately 100 d (De Pass et al. 1986b). EG in a wide range of concentrations is nonmutagenic (with and without metabolic activation) in test strains of the bacteria S. typhimurium and Es- cherichia coli (McCann et al. 1975, Zeiger et al. 1987, Mersch-Sundermann et

102 Spacecraft Water Exposure Guidelines al. 1994). It is also nonmutagenic in the yeast Schizosaccharomyces pombe at 0.5%, 2.0%, 5.0%, and 10%, (vol/vol) for 1 h, with and without activation, and there is no cytotoxicity (Abbondandolo et al. 1980) EG (3, 7, and 10 mM for 3 h) does not induce DNA strand breaks or cyto- toxicity in primary cultures of rat hepatocytes as determined by alkaline elution (Storer et al. 1996). At 50 and 500 µM, EG does not cause DNA-DNA or DNA- protein binding as determined by the DNA-cell-binding assay (Kubinski et al. 1981), nor does it inhibit cell-cell communication (Rosenkranz et al. 1997). In the fungus Neurospora crassa, EG is not mutagenic at 18% (vol/vol) for 4, 8, 12, 24, and 48 h, but it does reduce RNA translation by about one-half (Chaudhuri 1978). The non-Mendelian determinant, the psi-factor, in the yeast Saccharomyces cerevisiae is mutated from the + form to the – form by a high concentration (1.75 M) of EG. Rigorous experiments have shown that the psi- factor resides in the cytoplasm, not in the nucleus or in association with the mi- tochondrial DNA or double-stranded RNA (Singh et al. 1979). It suppresses the UAA codon and certain frameshift suppressors, and the data suggest that it af- fects the translation of RNA sequences into correct amino acid sequences to form protein. The above-cited investigations suggest that protein, not DNA, is the target of EG action. Early studies (D’Amato 1948, Maguire 1974) revealed that the mitotic and meiotic spindle is affected by EG in the same manner as by colchi- cine—namely, disorganization of the proteinaceous microtubules, so that chro- mosome movement at metaphase and anaphase is disturbed, leading to ane- uploidy (Griffiths 1979) or, at higher concentrations, to polyploidy. Some types of cells exposed to EG may also show chromosome stickiness, which can result in chromosome breakage when the chromatids separate at anaphase (D’Amato 1948). This result probably would account for any chromosome aberrations ob- served after EG treatment. Carcinogenicity No studies were found to suggest that oral exposure to EG could cause cancer. Reproductive Toxicity There is some evidence that EG can cause reproductive toxicity in at least one species. EG was given to male and female CD-1 mice in their drinking wa- ter at concentrations of 0%, 0.25%, 0.5%, or 1.0% for about 15 wk beginning at 11 wk of age. One week into the study, the mice were paired for breeding and the offspring of the matings were evaluated to assess reproductive performance (Lamb et al. 1985). Statistically significant effects were noted in the highest-

Ethylene Glycol 103 dose group. These effects included an 8% reduction in litters per pair, a 6% re- duction in the number of live pups per litter, and a 6% reduction in the weight of live pups. Offspring, still receiving EG at the appropriate concentration, from these matings (controls and high dose) were formed into 20 breeding pairs per group and allowed to mate for up to 7 d. The effects on reproductive perform- ance were more pronounced in this second-generation test. The percentage of pregnant mice per number cohabited fell from 80% in the controls to 61% in the treated group (Lamb et al. 1985). The findings were quite different from those of a study of F344 rats given doses slightly less than those in the mouse study. Three generations of male and female rats were exposed to EG in their food at 0.04, 0.2, and 1.0 g/kg/d (De- Pass et al. 1986b). The highest dose in the mouse study was equivalent to about 1.64 g/kg/d. There were no compound-related changes in fertility index, gesta- tional index, or pup survival index in the rats (DePass et al. 1986b). Developmental Toxicity Several investigators have shown that large oral doses of EG can cause morphologic abnormalities during fetal development. Fetuses from CD rats given gavage doses of 1.25, 2.5, and 5.0 g/kg/d on gestational days 6 to 15 showed excess postimplantation losses (high-dose group) and an increased per- centage of litters with one or more malformed live fetuses (Price et al. 1985). Likewise, fetuses from CD-1 mice given 0.75, 1.5, and 3.0 g/kg/d on gestational days 6 to 15 showed an increased frequency of malformations. The most com- mon malformations were craniofacial and neural-tube-closure defects and axial skeletal dysplasia (Price et al. 1985). Fetal abnormalities were also observed in offspring from the high-dose group of CD-1 mice given drinking water with 0%, 0.25%, 0.5%, or 1.0% EG for 15 wk before mating and during gestation (Lamb et al. 1985). The abnormalities included a reduction in the size of the skull bones, fused ribs, and abnormally shaped vertebrae. In an effort to determine a NOAEL for developmental toxicity in CD rats and CD-1 mice, both species were exposed on gestational days 6 to 15 by ga- vage to EG at 0, 0.15, 0.5, 1.0, and 2.5 g/kg/d (rats) or to 0, 0.05, 0.15, 0.5, and 1.5 (mice) g/kg/d (Neeper-Bradley et al. 1995). There was evidence of maternal toxicity in the highest-dose group of rats; however, there was no apparent evi- dence of maternal toxicity in mice. The EG NOAELs for developmental toxicity were 0.5 g/kg/d in rats and 0.15 g/kg/d in mice (Neeper-Bradley et al. 1995). These observations are consistent with observations reported by Price et al. (1985) at higher doses. Comparable findings have been reported in the same species and strain of rodent when the EG is administered by whole-body, aero- sol exposure; by nose-only, aerosol exposure; or by cutaneous application. The NOAELs in these studies for developmental toxicity were as follows—whole body exposure: CD rat, 150 mg/m3; CD-1 mice, 150 mg/m3; nose-only expo-

104 Spacecraft Water Exposure Guidelines sure: CD-1 mice, 1,000 mg/m3; cutaneous exposure under occluded dressing: CD-1 mice, >3,500 mg/kg/d (Tyl et. al. 1995a,b,c). At least one nonrodent species appears to be less susceptible to the devel- opmental toxicity of EG. Pregnant New Zealand White rabbits were exposed by gavage to EG at 0, 0.1, 0.5, 1.0, and 2.0 g/kg/d on gestational days 6 to 19 (Tyl et al., 1993). Severe maternal toxic effects (42% mortality) were observed in the high-dose group but not in the other groups. Despite this overt toxicity to dams, there were no developmental effects on the fetuses derived from any dosage group (Tyl et al. 1993). Carney et al. (1999) used the rat model for developmental toxicity of EG to determine whether glycolic acid or the metabolic acidosis caused the devel- opmental toxicity. With their approach, the peak blood glycolate concentrations could be maintained with or without metabolic acidosis. They injected sodium glycolate subcutaneously to achieve a high blood glycolate concentration with- out acidosis, and they administered EG and glycolic acid orally to produce com- parable blood glycolate peaks. They found a high prevalence of fetal malforma- tions in all three groups, leading them to conclude that glycolate is the proximate developmental toxicant. In a study of the metabolites of EG that may be involved in developmental toxicity in rats, Pottenger et al. (2001) found that nonlinear kinetics in the con- version of EG to glycolic acid were present at developmental toxicity NOAEL and lowest-observed-adverse-effect level (LOAEL) doses (EG range 500 to 1,000 mg/kg, respectively). Oxalic acid was found to be a minor metabolite in blood and urine. The authors suggest that this is evidence that glycolic acid plays a major role in EG’s developmental toxicity, that oxalic acid does not, and that EG doses must be quite high before sufficient glycolic acid is produced to elicit developmental toxicity (Pottenger et al. 2001). Space Flight Effects There are concerns that astronauts may be more susceptible to the forma- tion of renal stones as a result of the demineralization of calcium from bone tissue and subsequent release by the kidneys. Urinary calcium excretion, on average, doubled in Skylab astronauts, rising to 200 to 500 mg of calcium per day (Whedon et al. 1977). Although this factor suggests an increased risk of renal stones, there has been only one specific example of stones formed during space flight; one Russian flight was nearly aborted because of a stone, but just before deorbiting, the stone passed (Pietrzyk et al. 2007). Astronaut candidates are prescreened for susceptibility to renal stone formation and excluded from acceptance if they are stone formers. Thus, the rate of stone formation is much lower in astronauts (0.7 × 10-5 per person per day), whereas in the general popu- lation the rate in astronaut-matched controls is 1.14 × 10-5 per person per day (Pietrzyk et al. 2007). Another way to view the risk is to ask how much addi-

Ethylene Glycol 105 tional oxalate would be added to that excreted by the kidney each day from a given ingestion of EG. The normal oxalate load on the kidney is 24 mg/d. Inges- tion of 2.8 L of water with an EG concentration of 20 mg/L, the 100-d space- craft water exposure guideline (SWEG), and a conversion efficiency for EG to oxalate of 0.023 (Reif 1950) adds only 1.3 mg/d. This is only 5% of the usual load. Thus, ingestion of small amounts of EG should not increase the risk of renal stone formation, provided adequate fluid intake is monitored (by paying attention to the pale color of urine); therefore, this factor is not considered in the rationale for water quality values near 20 mg/L. All crewmembers lose about 10% of their RBC mass within a few days of starting to live in microgravity (Huntoon et al. 1994), which may make them more susceptible to any hematotoxic action of EG. Synergistic Effects No specific compounds are known to potentiate the toxicity of EG; how- ever, a number of compounds counteract the acute effects of ingestion of life- threatening amounts of EG. Ethanol, 4-methylpyrazole, and 1,3-butanediol in- hibit EG toxicity by interfering with alcohol dehydrogenase and CYPIIE1 activ- ity, which reduces the formation of more toxic metabolites (ATSDR 1997). In experimental animals, magnesium and vitamin B6 have been found to reduce the injury caused by ingesting EG (Gershoff and Andrus 1962). LIMITS SET BY OTHER ORGANIZATIONS Inspection of Table 3-3 reveals a fairly narrow range of water quality lim- its for most applications involving long-term exposures to EG. The range is from 5 to 20 mg/L for the U.S. Environmental Protection Agency (EPA) and five of eight states listed by EPA sources (EPA 1993). NASA used the EPA lifetime health advisory (HA) of 7 mg/L as its standard for potable water when EG was a concern on the Mir space station. The lowest limits come from New Jersey and Connecticut. 1-d Health Advisory The 1-d HA is listed as 20 mg/L (EPA 1996); it was apparently based on the rationale provided in an earlier document (EPA 1987). According to the 1987 document, the 1-d HA was based on a study by Reif (1950) in which the investigator ingested EG at 190 mg/kg with no apparent effect. The calculation is as follows:

106 Spacecraft Water Exposure Guidelines TABLE 3-3 Water Quality Limits Set by Other Organizations Agency or Standard Set Limit Reference Russian Ministry of Health Manned spacecraft 11 mg/L Gosstandart 1995 EPA Health Advisory Child, 1 d 20 mg/L EPA 1987, 1993, 1996 Child, 10 d 6 mg/L Child, 7 y 6 mg/L Adult, 7 y 20 mg/L Adult, 70 y 7 mg/L EPA RfD (oral) 2 mg/kg/d (70 mg/L)a EPA 1992 ATSDR Minimum Risk Level (14 d to 1 y) 2 mg/kg/d (70 mg/L)a ASTDR 1997 State Drinking Water Guidelines Five states 5.5-10 mg/L EPA 1993 Connecticut 0.1 mg/L New Jersey 0.29 mg/L Massachusetts ORSGL 14 mg/L a Assumes a water consumption of 2 L/d by a 70-kg person. Abbreviations: EPA, U.S. Environmental Protection Agency; ORSGL, Office of Re- search and Standards Guideline; RfD, reference dose. 1-d HA = (190 mg/kg/d × 10 kg)/100 × 1 L/d = 19 mg/L. The body weight (10 kg) and ingestion volume (1 L/d) are for a child, and the uncertainty factor of 100 was applied according to guidelines used at the time. 10-d Health Advisory In 1987, EPA determined that there were insufficient data to set a HA for 10 d of ingestion of water containing EG; however, it determined that the longer-term HA can serve as a conservative estimate of what the 10-d HA ought to be. The longer-term limit was calculated to be 5.5 mg/L (see below). The 1996 EPA table of health advisories lists a value of 6 mg/L for 10 d of ingestion by a child. Longer-Term Health Advisory The longer-term HA, which applies to ingestion up to 7 y, was calculated for adults and children based on the NOAEL of 55 mg/kg/d reported in a 3-y study of rhesus monkeys (Blood et al. 1962; EPA 1987). The longer-term HA for children was calculated as follows:

Ethylene Glycol 107 Longer-term HA = (55 mg/kg/d × 10 kg)/(100 × 1 L/d) = 5.5 mg/L (child), where 100 is an uncertainty factor based on guidelines used at the time, 10 kg is the typical weight of a child, and 1 L/d is the volume of water ingested each day. For an adult the calculation was as follows: Longer-term HA = (55 mg/kg/d × 70 kg)/(100 × 2 L/d) = 19 mg/L (adult), where appropriate body weights and ingestion volumes for an adult were used in place of those for a child. The values calculated as shown above were apparently rounded to 6 mg/L for a child and to 20 mg/L for an adult (EPA 1996). Lifetime Health Advisory EPA calculated the lifetime (70 y) HA from the reference dose (RfD), which was 1 mg/kg/d based on the 100-mg/kg/d NOAEL found in rats fed EG for up to 2 y (Blood 1965; EPA 1987). The NOAEL was divided by an uncer- tainty factor of 100 to obtain the RfD. The lifetime HA was calculated as fol- lows: Lifetime HA = RfD × (70 kg/2 L/d) × 0.2 = 7 mg/L, where 0.2 (or 20%) was considered the relative source contribution (EPA 1987). The relative source contribution is the fraction of EG present in drinking water as a portion of EG coming from all sources. In some cases, this is measured; however, for EG the data were insufficient—hence, the default assumption of 20% for synthetic organic chemicals was used. Guidelines from Selected States Certain states appear to have health guidelines significantly different than the EPA limits. The guideline from the Massachusetts Office of Research and Standards Guideline (ORSGL) was based on an RfD of 2 mg/kg/d as given by EPA (1992), with the calculation as follows: ORSGL = (2 mg/kg/d × 70 kg × 0.2)/2 L/d = 14 mg/L. The value of 0.29 mg/L listed by the EPA (1993) was never an officially promulgated standard for the state of New Jersey. A more recent proposed stan- dard by New Jersey, based on newer data, is 3 mg/L; however, this has not been officially adopted and the documentation is in draft form only. The low value of

108 Spacecraft Water Exposure Guidelines 0.1 mg/L from Connecticut was set in 1979 based on earlier data, and the docu- mentation of that value is unavailable. In any case, Connecticut is considering dropping the limit because it has never been used. Rationale for Guidelines That Are Different from Other Limits The exposure guidelines (Table 3-4) for 100 d (20 mg/L) and 1,000 d (4 mg/L) are generally comparable to most other established levels (Table 3-3). For example, the 7-y HA for adults is 20 mg/L. The proposed 10-d SWEG (140 mg/l) is well above the 10-d EPA HA, but the latter applies to children, whereas the SWEG applies to healthy adults. It seems that if adults can tolerate 20 mg/L for 7 y, then they can tolerate a 7-fold higher concentration for only 10 d. Given this difference in target populations, the difference in guidelines seems suitable. RATIONALE FOR LIMITS The toxicity database on EG is sufficiently complete to set SWEGs with confidence that the values are protective of health without being overly conser- vative. The database consists of case reports of acute human ingestions, lethality studies in a variety of species, drinking water studies in rodents and primates, and feed studies in rodents and primates. The most useful studies involve ro- dents administered several doses in large groups, with evaluation of a broad range of toxicity end points. In general, the guidelines given by the National Research Council Committee on Toxicology (NRC 2000) were applied to the data. Those recommendations do not include a factor for interindividual varia- tion because astronauts come from a population of very healthy adults. How- ever, if there are known variations in the metabolism of the compound or sus- ceptibility to the compound regardless of health status, then an interindividual factor can be applied. For EG, an interindividual factor of 3 was applied because two of the enzymes involved in the metabolism of EG are known to have vari- able activities based on genetic variants in the human population. In particular, TABLE 3-4 Spacecraft Water Exposure Guidelines for Ethylene Glycol Duration of Consumption, d Guideline, mg/L Toxicity Target for Protection 1 270 Kidney, central nervous system 10 140 Kidney, tubular degeneration 100 20 Kidney, tubular degeneration 1,000 4 Kidney, tubular degeneration

Ethylene Glycol 109 many persons of Asian descent may have increased susceptibility to EG, just as they are more susceptible to the adverse effects of ethanol. The estimates were based on a direct water consumption rate of 2 L/d and an additional volume of 0.8 L/d to reconstitute food aboard the International Space Station. For part of the 10- and 90-d data, the conventional NOAEL approach and the benchmark dose (BMD) approach were applied. The latter approach sometimes resulted in acceptable concentrations (ACs) severalfold lower than those based on the con- ventional NOAEL approach. In addition, any concomitant inhalation exposure to EG must be considered when one is assessing the health risk from EG in drinking water. Guideline for 1 d The 1-d guideline was based on an estimate of the minimum lethal con- centration of 1.6 g/kg provided by Gessner et al. (1961). There was an older estimate of the minimum lethal concentration (1.1 g/kg) in the 1930s, but the later estimate was presumed to be based on more experience. The estimate seems consistent with the few case reports with information on the amount of EG ingested. For example, two cases were reported that led to death 36 or 72 h after ingestion of approximately 150 mL of EG (Walton 1978). The body weights of the victims were not mentioned, but if one assumes a 70-kg body weight, then the dose was about 2.4 g/kg. Nonlethal ingestions between 90 and 200 mL (average 150 mL) over 3 d have been reported for a group of five per- sons 12 to 15 y old (Moriarty and McDonald 1974). Three of the five were hos- pitalized with CNS symptoms, gastrointestinal symptoms, metabolic acidosis, and abnormal urinalysis, but all recovered. Taking an average daily dose for the 3 d of ingestion and assuming a 50-kg body weight, the nonlethal amount was 1.1 g/kg. Hence, the 1.6 g/kg estimate provided by Gessner et al. (1961) seems consistent with the case reports available. On the basis of previous discussions by the subcommittee (see Garcia and James 2000, p. 321, indicating factors from 30 to 50 for estimating a NOAEL from a 50% lethal concentration), a factor of 5 was used to convert this mini- mum lethal estimate to a LOAEL for renal effects (renal damage is often the cause of death) and a factor of 10 was used to estimate a NOAEL from the LOAEL. Finally, the large interindividual genetic differences in alcohol dehy- drogenase and aldehyde dehydrogenase suggest that some factor would be ap- propriate to deal with these known variations. An uncertainty factor of 3 was selected for interindividual metabolic variations that could influence a person’s susceptibility to the toxic action of EG. A factor as large as 10 was not consid- ered necessary because of the consistently healthy status of astronauts. The 1-d AC for a 70-kg person to avoid CNS and renal effects from EG in drinking wa- ter consumed at a rate of 2.8 L/d was calculated as follows:

110 Spacecraft Water Exposure Guidelines 1-d AC(CNS, renal failure) = 1.6 g/kg/d(lethal) × 1/5(lethal to LOAEL) × 1/10(LOAEL to NOAEL) × 1/3(interindividual variability) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 0.27 g/L. This amount (0.27 g/L × 2.8 L/d = 0.75 g/d) is comparable to the amount that would be taken up by inhalation of EG at the 24-h SMAC concentration of 60 mg/m3, which would yield an uptake of 0.7 g/d in a person inhaling 20 m3/d at a retention of 60% (Wong 1996). The 4-d exposure data of Hong et al. (1988) showing 14-d reversible ef- fects on bone marrow progenitor cells in females and apparently lasting effects in males were not used because they seem inconsistent with the report that much higher, chronic doses in the same strain of mouse do not affect the RBC or WBC counts in the circulation (NTP 1993). Guideline for 10 d ACs were derived for renal and hematologic toxicity based on findings in rodents. Data from Robinson et al. (1990) suggest a NOAEL of 0.5% for renal lesions in male rats drinking EG-contaminated water for 10 d. A 0.5% (vol/vol) concentration in water represents an average consumption of 650 mg/kg/d, so the AC was calculated as follows: 10-d AC(renal effects) = 650 mg/kg/d(NOAEL) × 1/10(species) × 1/3(interindividual variability) × 1/3(spaceflight) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 180 mg/L. The spaceflight factor of 1/3 reduces the risk of renal stone formation due to excess oxalate produced from EG metabolism. In the same 10-d study, the NOAEL for effects on blood cells in female rats was 2.0% or an average con- sumption of 2,950 mg/kg/d in drinking water. Because about a 10% loss of RBC mass occurs in astronauts within a few days of exposure to microgravity, they have been considered a susceptible population for hematotoxicants; a factor of 3 was applied to address this putative susceptibility. The estimated AC was as follows: 10-d AC(blood effects) = 2,950 mg/kg/d(NOAEL) × 1/10(species) × 1/3(interindividual variability) × 1/3(spaceflight) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 820 mg/L. Findings from Gershoff and Andrus (1962) were not used because they began their study with weanling rats, the diet was synthetic, and the duration was 28 d, rather than 10 d. The observations of renal toxicity in Macaques re- ported by Roberts and Seibold (1969) were not used because of the small num- ber of animals involved at any specific dose and the lack of control animals.

Ethylene Glycol 111 Guideline for 100 d At 100 days of EG ingestion, the risk of liver injury is added to the risks from kidney injury and hematologic effects. The AC to avoid renal injury from 100 d of ingestion was based on the LOAEL in male rats that drank water con- taining 0.25% (205 mg/kg/d) EG for 90 d (Robinson et al. 1990). The commit- tee recommended that this value be considered the LOAEL because the inci- dence of tubular degeneration was 50% in this dose group and it was only 30% in the control group. Statistical significance was not achieved because of the relatively small number of animals in each group. A factor of only 3 was rec- ommended to extrapolate from the LOAEL to a NOAEL because the LOAEL was determined by an extremely conservative approach (taking 0.25% as the LOAEL). Factors for interspecies extrapolation (10), interindividual variability (3), and time (100 d/90 d) were applied to the LOAEL to estimate the 100-d AC (renal injury) of 51 mg/L as follows: 100-d AC(renal injury) = 205 mg/kg/d(LOAEL) × 1/10(species) × 1/3(interindividual variability) × 90 d/100 d(time extrapolation) × 1/3(LOAEL to NOAEL) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 51 mg/L. To estimate the 100-d AC to avoid liver toxicity, the same factors were applied to the NOAEL of 3 g/kg/d found in a subchronic feeding study (Melnick 1984, NTP 1993). The estimate was as follows: 100-d AC(liver effects) = 3 g/kg/d(NOAEL) × 1/10(species) × 1/3(interindividual variability) × 90 d/100 d(time extrapolation) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 2.3 g/L. The NOAEL for decreased WBC count in female rats ingesting EG- contaminated drinking water for 90 d was 1.0% (1,150 mg/kg/d) (Robinson et al. 1990). Applying the same factors as those used for renal effects, but with an added safety factor of 3 for spaceflight effects (in this case putative changes in immune function), the 100-d AC (hematologic/immune effects) was 290 mg/L calculated as follows: 100-d AC(hematotoxicity) = 1,150 mg/kg/d(NOAEL) × 1/10(species) × 1/3(interindividual variabity)× 1/3(spaceflight) × 90 d/100 d(time extrapolation) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 290 mg/L. Guideline for 1,000 d The approach used to estimate ACs for 1,000 d was parallel to that used for the 100-d estimates. The starting point was the NOAEL (0.2 g/kg/d) found

112 Spacecraft Water Exposure Guidelines for renal, liver, and hematologic effects in the 2-y feeding study of DePass et al. (1986a). The committee advised against using a time factor for the difference in the number of exposure days between the study and the SWEG exposure time; otherwise, the factors were identical to the 90-d factors. For example, the calcu- lation for effects on blood cells was as follows: 1,000-d AC(blood cells) = 0.2 g/kg/d(NOAEL) × 1/10(species) × 1/3(interindividual variability) × 1/3(spaceflight) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 55 mg/L. The estimate for liver and renal effects (170 mg/L) was 3-fold higher than for hematologic effects because no spaceflight (microgravity) factor was ap- plied. BMD modeling was unsuitable because there were no intermediate dose effects. Typically, there were pronounced effects at 1 g/kg/d and no observed effects at 0.2 g/kg/d and below. This type of dose-response profile does not re- sult in meaningful BMD estimates. By using the BMD approach (see below), the estimates for 10- and 100-d exposures in water were comparable to the 7- to 180-d SMAC of 13 mg/m3 (Wong 1996). Using a breathing rate of 20 m3/d and 60% uptake of EG vapor gives a daily uptake of 0.16 g/d, whereas the daily loads from ingesting 2.8 L of water at the SWEG would be 0.4 and 0.06 g/d for 10 and 100 d of consumption, respectively. We must recall that the 10-d SWEG is a contingency value (em- bodies a higher risk of slight effects), whereas the 7-d SMAC is for nominal operations, so the difference between the load of 0.4 g/d from the 10-d SWEG and 0.16 g/d from the 7-d SMAC makes sense. BMD Analysis of Kidney Lesions in Rats Biologic Considerations on Model Selection The lesions noted in the 10- and 90-d rat drinking-water studies by Robin- son et al. (1990) were renal tubular degeneration, intratubular crystals, and subacute inflammation (90 d only). Males were more sensitive than females, so our analyses focus on them. The mechanism of formation of these lesions at the cellular level is unclear; however, it is clear that one or more of the metabolites of EG (oxalic acid, glycolic acid, or glucoaldehyde) mediates the injury. The active metabolite must be present at the site of action in the kidney and chemi- cally react with a sufficient number of molecules composing critical cellular structures or functions to produce observable cell degeneration. Likewise, crys- tal formation depends on chemical reactions and subsequent precipitation in the renal tubules at a specific pH to produce a microscopically detectable “lesion.” Under these conditions, the appropriate model for either end point is one de- rived from chemical kinetic theory (Hartung 1987; Faustmann and Omenn 2001). We selected the log-logistic model as most likely to be applicable to re-

Ethylene Glycol 113 nal tubular degeneration or intratubular crystal formation. This model defines sigmoidal curves that are symmetric around the 50% response level. The model tends to yield intermediate estimates of the virtually safe dose from dose- response curves when compared with estimates from other commonly used models (Brown 1984). In addition, we selected the dose as the average con- sumed by the group during the study rather than the concentration of EG in the drinking water. Database and BMD Analyses for 10 d The databases for the end points and dosages for 10-d exposures are given in Table 3-5. The BMD analysis for these end points using the log-logistic model is shown in Table 3-6. Conversion from mg/kg/d back to the percent of EG in the water was done using a divisor of 1,320, which was derived from average ratios in Table 3-5 for concentrations of 0.5% to 2.0%. TABLE 3-5 Kidney Lesions in Male Rats Exposed for 10 d to EG in Their Drinking Water Number of Renal Tubular Intratubular Dose, % Dose, mg/kg/d Rats Degeneration Crystals 0 0 10 2 0 0.5 650 10 2 0 1.0 1,340 10 2 1 2.0 2,620 10 6 5 4.0 5,280 10 9 7 TABLE 3-6 Log-Logistic Model of Kidney Lesions Found in Rats Drinking EG-Contaminated Water for 10 d Parameter/End Point Renal Tubular Degeneration Intratubular Crystals BMD10 1,410 mg/kg/d (1.07%) 1,230 mg/kg/d (0.93%) BMDL10 520a mg/kg/d (0.40%) 590 mg/kg/d (0.45%) BMD01 690 mg/kg/d (0.52%) 440 mg/kg/d (0.33%) BMDL01 100 mg/kg/d (0.08%) 92 mg/kg/d (0.07%) P value (Pearson χ2) 0.87 0.79 AIC 56.26 37.83 a Point of departure. Abbreviations: AIC, Akaike Information Criterion; BMD10, the maximum-likelihood dose expected to give a 10% response; BMD01, the maximum-likelihood dose expected to give a 1% response; BMDL10, the 95% lower confidence limit of the BMD10; BMDL01, the 95% lower confidence limit of the BMD01.

114 Spacecraft Water Exposure Guidelines The renal tubular degeneration (RTD) and intratubular crystal (IC) data show an excellent fit to the log-logistic model (P = 0.87 or 0.79). The RTD cal- culations are close to those published on the same data set but analyzed with the percent of EG instead of the average amount ingested at each dose. The pub- lished log-logistic numbers comparable to those in parentheses in the second column of Table 3-6 were 1.15%, 0.43%, 0.55%, and 0.09% (Bailer et al. 2005a). The Bayesian model averaging (BMA) for nine models gave the follow- ing results: 0.83%, 0.45%, 0.23%, and 0.09%, respectively. The IC calculations in Table 3-6 also agree extremely well with those published for the same data set but using the percent of EG in the water instead of the average consumption rate (Bailer et al. 2005b). We note in addition that the BMA performed by the same investigators using the IC data yields values close to those resulting from choosing the model by mechanistic arguments a priori as done here. The four BMA estimates were 0.91%, 0.54%, 0.23%, and 0.10% for the combination of 10 models (Bailer et al. 2005b). Based on committee recommendations, the lowest log-logistic BMDL10 was used as the point of departure for our calcula- tions of renal injury risk because with such a small n value in each group, it is unlikely that the BMD01 has sufficient precision. The BMDL10 of 520 mg/kg/d for RTD was used. 10-d AC(renal effects) = 520 mg/kg/d(BMDL10) × 1/10(species) × 1/3(interindividual variability) × 1/3(spaceflight) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 140 mg/L. The spaceflight factor of 3 was included to reduce the risk that the oxalate produced from EG at 430 mg/L (the concentration without the factor) would increase the likelihood of a renal stone forming in 10 d. This result is not very different than the result (180 mg/L) from taking 0.5% (650 mg/kg/d) as a NOAEL (see guideline for 10 d). Database and BMD Analysis for 90 d For consistency, a similar approach was applied to the kidney lesions found in rats ingesting EG-contaminated water for 90 d. The database for the observed effects is presented in Table 3-7. The BMD analysis for these data is shown in Table 3-8. The percent dose in columns 2 and 3 was estimated from the average dose in mg/kg/d using a factor of 810, which was found from the ratios at 0.25% and 0.5% in Table 3-7. Based on visual inspection, the log-logistic fit to the RTD data is very good, the fit to the IC data is excellent, and the fit to the SI data is marginal (see Appendix to view the quality of fit to the data). We do not consider the model fit to the SI data to be informative because of response variations that suggest a

Ethylene Glycol 115 TABLE 3-7 Lesions Found in Male Rats Ingesting EG-Contaminated Water for 90 d Dose, Number Number Number Number Dose, % mg/kg/d of Rats with RTD with IC with SI 0 0 10 3 0 5 0.25 200 10 5 0 3 0.5 410 10 5 0 7 1.0 950 10 8 8 7 2.0 3,130 9 9 9 9 Abbreviations: IC, intratubular crystal; RTD, renal tubular degeneration; SI, subacute inflammation. TABLE 3-8 BMD Analysis for Lesions Seen in Rats Ingesting EG- Contaminated Water for 90 da Parameter/Lesion RTD IC SI BMD10 300 mg/kg/d 780 mg/kg/d 320 mg/kg/d (0.39%) (0.37%) (0.96%) BMDL10 27b mg/kg/d 390 mg/kg/d 46 mg/kg/d (0.06%) (0.03%) (0.48%) BMD01 120 mg/kg/d 680 mg/kg/d 115 mg/kg/d (0.14%) (0.15%) (0.84%) BMDL01 2.5 mg/kg/d 210 mg/kg/d 4 mg/kg/d (0.005%) (0.003%) (0.26%) P value (Pearson χ2) 0.68 1 0.25 AIC 56.83 12.008 59.56 a The appendix presents curve fittings for RTD (Figure 3-2), IC (Figure 3-3), and SI (Fig- ure 3-4). b Point of departure. Abbreviations: AIC, Akaike Information Criterion; BMD10, the maximum-likelihood dose expected to give a 10% response; BMD01, the maximum-likelihood dose expected to give a 1% response; BMDL10, the 95% lower confidence limit of the BMD10; BMDL01, the 95% lower confidence limit of the BMD01; IC, intratubular crystal; RTD, renal tubular degeneration; SI, subacute inflammation. response reversal between the control and low-dose groups. The low BMDL10 was selected as the point of departure for calculation of the AC for renal effects. 100-d AC(renal effects) = 27 mg/kg/d(BMDL10) × 1/10(species) × 1/3(interindividual variability) × 90 d/100 d(time extrapolation) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 20 mg/L.

116 Spacecraft Water Exposure Guidelines This result is well below the result (51 mg/L) if we begin with the lowest dose 0.25% (205 mg/kg/d) as a LOAEL and use it as the point of departure (see guideline for 100 d). Application of BMD Analyses to Predict a 1,000-d AC for Kidney Injury Comparing the third columns in Tables 3-6 and 3-8 reveals that the inci- dence of IC does not increase with increasing exposure time. The comparable benchmark estimates are roughly within a factor of 2. If this were the only ad- verse effect in the kidney, then the 1,000-d AC would be the same as the 10-d AC. However, inspection of the second columns in Tables 3-6 and 3-8 shows that the risk of RTD does increase with time of exposure. On the basis of the central estimates for a 10% risk (BMD10) for 10 and 90 d, we note that the value drops 5-fold from 1,410 to 300 as the time of exposure increases almost 10-fold from 10 to 90 d. To estimate the AC for 1,000 d (a 10-fold increase in ingestion time), we divide the 100-d AC of 20 mg/L by 5 as follows: 1,000-d AC(renal injury) = 20 mg/L(10-d AC) × 1/5(increased exposure time) = 4 mg/L. The summary of AC calculations and final SWEGs are given in Table 3-9.

TABLE 3-9 Acceptable Concentrations of EG in Drinking Water to Prevent Adverse Effects Uncertainty Factors Acceptable Concentrations, mg/L Data/ Sex/ Micro- Inter- Exposure Reference Species NOAEL Species gravity individual Time 1d 10 d 100 d 1,000 d Reference Kidney Minimum lethal estimate M/F 50 1 1 3 1 270 — — — Gessner et 1.6 g/kg (apply to CNS also) Human al. 1961 10-d NOAEL renal lesions, M/SD 1 10 3 3 1 — 180 — — Robinson et 0.5% in drinking water rats al. 1990 10-d BMDL10 = 520 mg/kg/d M/SD 1 10 3 3 1 — 140 — — Robinson et (IC) rats al. 1990 90-d LOAEL renal lesions, M/SD 3 10 1 3 1.1 — — 51 — Robinson et 0.25 % in drinking water rats al. 1990 90-d BMDL10 = 27 mg/kg/d M/SD 1 10 1 3 1.1 — — 20 4 Robinson et (IC) rats al. 1990 730-d NOAEL renal lesions, M/F344 1 10 1 3 1 — — — 170 DePass et al. 0.2 g/kg/d feed rats 1986a Liver 91-d NOAEL centrilobular M/F344 1 10 1 3 1.1 — — 2,300 — Melnick 1984 necrosis, 3 g/kg/d feed rats NTP 1993 730-d NOAEL fatty change, F/F344 1 10 1 3 1 — — — 170 DePass et al. monocyte infil., granulomas, rats 1986a 0.2 g/kg/d feed (Continued) 117

TABLE 3-9 Continued 118 Data/ Uncertainty Factors Acceptable Concentrations, mg/L Reference Sex/ Micro- Inter- Exposure Species NOAEL Species gravity individual Time 1d 10 d 100 d 1,000 d Reference Liver (Continued) 10-d NOAEL on RBC/WBC F/SD 1 10 3 3 1 — 820 — — Robinson indices, 2.0% (22 g/L) rats et al. 1990 drinking water 90-d NOAEL on WBC count, F/SD 1 10 3 3 1.1 — 290 — Robinson 1.0% (11 g/L) drinking water rats et al. 1990 730-d NOAEL RBC/WBC M/F344 1 10 3 3 1 — — — 55 DePass et indices, 0.2 g/kg/d feed rats al. 1986a SWEG 270 140 20 4 Abbreviations: F, female; M, male; SD, Sprague-Dawley; —, not calculated.

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124 Spacecraft Water Exposure Guidelines APPENDIX Log-Logistic Model with 0.95 Confidence Level Log-Logistic 1 0.8 Fraction Affected 0.6 0.4 0.2 0 0 500 1000 1500 2000 2500 3000 BMDL BMD Dose 12:09 04/19 2007 FIGURE 3-2 Curve for 90-d renal tubular degeneration. P-value = 0.675 Specified effect = 0.1 Risk Type = Extra risk BMD = 302 BMDL = 27.4 Log-Logistic Model with 0.95 Confidence Level Log-Logistic 1 0.8 Fraction Affected 0.6 0.4 0.2 0 0 500 1000 1500 2000 2500 3000 BMDL BMD Dose 12:14 04/19 2007 FIGURE 3-3 Curve for 90-d tubular crystal formation. P-value = 1.0000 Specified effect = 0.1 Risk Type = Extra risk BMD = 779 BMDL = 391

Ethylene Glycol 125 Log-Logistic Model with 0.95 Confidence Level Log-Logistic 1 0.8 Fraction Affected 0.6 0.4 0.2 0 0 500 1000 1500 2000 2500 3000 BMDL BMD Dose 12:04 04/19 2007 FIGURE 3-4 Curve for 90-d subacute inflammation. p value = 0.248 Specified effect = 0.1 Risk Type = Extra risk BMD = 317 BMDL = 46.5

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NASA maintains an active interest in the environmental conditions associated with living and working in spacecraft and identifying hazards that might adversely affect the health and well-being of crew members. Despite major engineering advances in controlling the spacecraft environment, some water and air contamination is inevitable. Several hundred chemical species are likely to be found in the closed environment of the spacecraft, and as the frequency, complexity, and duration of human space flight increase, identifying and understanding significant health hazards will become more complicated and more critical for the success of the missions.

To protect space crews from contaminants in potable and hygiene water, NASA requested that the National Research Council NRC provide guidance on how to develop water exposure guidelines and subsequently review NASA's development of the exposure guidelines for specific chemicals. This book presents spacecraft water exposure guidelines (SWEGs) for antimony, benzene, ethylene glycol, methanol, methyl ethyl ketone, and propylene glycol.

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