OCCURRENCE AND USE
EG has many uses. It is used as antifreeze in motor vehicles and in hydraulic 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 problem 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,
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 86
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 viscous, 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 197.4°C Melting point −13.4°C Specific gravity 1.11 (at 25°C) 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 hydraulic 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 problem 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,
OCR for page 87
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 condensate and 46 mg/L in the recycled water (Lizanna Pierre, Wyle Laboratories, personal commun., 1999). Even though EG is not used in coolant loops in the International 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 generally understood for many years, but new discoveries have been reported in the past few years. The understanding of the behavior of EG has important implications for treating acute poisonings and for understanding the metabolic pathways 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 absorbed 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
OCR for page 88
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 disturbances. The metabolism has been summarized as shown in Figure 3-1 (ATSDR 1997). EG is oxidized by alcohol dehydrogenase to glycoaldehyde, which is oxidized by aldehyde oxidase or aldehyde dehydrogenase to glycolic acid and glyoxal. 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 involving 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 metabolized. Alcohol dehydrogenase is a dimer with multiple molecular forms determined 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 expect considerable interindividual variability in the metabolism of EG. Likewise, aldehyde dehydrogenase has a number of different molecular forms with different catalytic capabilities (Thomasson et al. 1993), which could further contribute to interindividual variation in susceptibility to high oral doses of EG. Genetic polymorphisms in the human population can affect the susceptibility of individuals to xenobiotics such as EG when those polymorphisms control 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. Because astronauts are not screened for this genetic factor, one must assume that some individual astronauts are homozygous for the nonfunctional allele. Depending 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.
OCR for page 89
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 dehydrogenase 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 reduces the toxicity of EG, the authors suggested that the free radicals do not contribute 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.
OCR for page 90
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 the formation of H2O2 (Kukielka and Cederbaum 1995), it likely involves the formation of a reactive species and an EG radical intermediate. Thus, the protective 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 poisoning can be improved by measuring glycolic acid rather than EG in body fluids, especially if the ingestion occurred more than 24 h before hospital admission (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 causing 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 produced 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 minutes (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 authors concluded that glycoaldehyde and glyoxylate, because they produced profound ATP depletion and lactate dehydrogenase release in the PTS, are the primary metabolites responsible for EG nephrotoxicity. One must simply conclude that there is no consensus on which EG metabolite is responsible for the toxic effects on the kidney. Metabolites and developmental 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
OCR for page 91
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 prolonged 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 excreted as glycolate in the urine (Marshall 1982). The renal toxicity occurs as the detoxification pathways are overwhelmed and more toxic metabolites are eliminated 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 poisonings 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
OCR for page 92
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 sequence 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 progress 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 metabolites (Parry and Wallach 1974). The second stage lasts from 12 to 36 h after ingestion and involves cardiopulmonary effects. Clinical findings can include tachypnea, tachycardia, hypotension, 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 oxalate 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 presence 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 calcium 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 neurologic 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
OCR for page 93
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 3-2 Summary of Toxic Effects Dose or Concentration Route or 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 for 4 d Oral gavage B6C3F1 mouse, M/F Bone marrow hypocellularity, suppression of progenitor colony formation, and erythropoiesis. All reversible in females. Hong et al. 1988
OCR for page 94
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Dose or Concentration Route or Exposure Species Effects Reference Short-term Dosages (6-30 d) 0.25% 28 d DW Charles River rat, M, n=6 Renal lesions (weanlings). Gershoff and Andrus 1962 0.5%-4.0% 10 d DW SD rat, F, n=10 Increased incidence or severity of renal lesions, decreased RBC indices and WBC count in 4% group NOAEL was 2%.a Robinson et al. 1990 0.5%-4.0% 10 d DW SD rat, M, n =10 Increased incidence or severity of renal lesions at 2% and 4%; NOAEL was 0.5%.a Robinson et al. 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 DW Macaque, M, n=2-7 Anemia, azotemia. Roberts and 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 incidence at all concentrations; LOAEL was 0.25%.a Robinson et al. 1990 0.5%-4% 90 d DW SD rat, F, n=10 8/10 died at highest dose; renal lesions increased in severity or incidence in 2% and 4% groups; decreased leukocytes in all groups except 1% group, which was taken as the NOAEL.a Robinson et al. 1990 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, M, n=10 No clinical signs, no changes in clinical pathology values, nephrosis, and centrilobular degeneration in liver of 2.5% and 5% groups. NOAEL was 1.25% (3 g/kg/d)a for these effects. Melnick 1984 NTP 1993
OCR for page 95
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 0.3%-5% 94 d feed B6C3F1 mouse, F, n=10 NOAEL for all effects. Melnick 1984 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, creatinine, and renal crystals. Melnick 1984 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, M, n=2 NOAEL for histopathology (2/2) of many organs including kidney. Blood et al. 1962 0.5% 3 y feed Rhesus monkey, F, n=1 NOAEL for histopathology (1/1) of many organs including kidney. Blood et al. 1962 0.2% 2 y feed SD rat, M, n=16 NOAEL for renal calcification, effects seen at 0.5%, 1%, and 4%. Increased mortality in 1% and 4% groups. Normal hematology. Blood 1965 0.5% 2 y feed SD rat, F, n=16 NOAEL for renal calcification, effects seen at 1% and 4%. Increased mortality in 4% group. Normal hematology. Blood 1965 1%-2% 2 y feed Albino rat, M/F, n =10 Renal oxalate crystals, atrophy, fibrosis. Liver centrilobular atrophy, bile duct proliferation, fatty changes, bladder stone in males. Morris et al. 1942 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 infiltrate, and granulomas in liver; 1.0 g/kg/d was NOAEL for all other effects including neoplasia. DePass et al. 1986a 0.04-1.0 g/kg/d 2 y feed F344 rat, M, n=130 NOAEL 0.2 g/kg/da renal injury (creatinine, BUN, lesions) mineralization of heart, lung stomach, and for parathyroid 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 DePass et al. 1986a
OCR for page 96
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Dose or Concentration Route or Exposure Species Effects Reference 1.0 g/kg/d 2 y feed CD1 mouse, M/F, n=80 NOAEL for clinical signs, histopathology, and neoplasia. DePass et al. 1986a 0.62%-2.5% (1.5-6 g/kg/d) 2 y feed B6C3F1 mouse, M, n=50 NOAEL for clinical pathology in all groups. 1.5 g/kg/d NOAEL for liver hyaline degeneration. NOAEL for neoplasms in all groups. Nephropathy in high-dose group at 15-month interim sacrifice. NTP 1993 1.25%-5% (3-12 g/kg/d) 2 y feed B6C3F1 mouse, F, n=50 NOAEL for clinical pathology in all groups 1.25%. LOAEL lung arterial medial hyperplasia (10/50 versus 3/50 in controls). 1.25% NOAEL for liver hyaline degeneration. NOAEL for neoplasms in all groups. NTP 1993 aResult was used as abasis 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.
OCR for page 115
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 3-7 Lesions Found in Male Rats Ingesting EG-Contaminated Water for 90 d Dose, % Dose, mg/kg/d Number of Rats Number with RTD Number with IC Number 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 (0.37%) 780 mg/kg/d (0.96%) 320 mg/kg/d (0.39%) BMDL10 27b mg/kg/d (0.03%) 390 mg/kg/d (0.48%) 46 mg/kg/d (0.06%) BMD01 120 mg/kg/d (0.15%) 680 mg/kg/d (0.84%) 115 mg/kg/d (0.14%) BMDL01 2.5 mg/kg/d (0.003%) 210 mg/kg/d (0.26%) 4 mg/kg/d (0.005%) P value (Pearson χ2) 0.68 1 0.25 AIC 56.83 12.008 59.56 aThe appendix presents curve fittings for RTD (Figure 3-2), IC (Figure 3-3), and SI (Figure 3-4). bPoint 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.
OCR for page 116
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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 incidence 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 adverse 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: The summary of AC calculations and final SWEGs are given in Table 3-9.
OCR for page 117
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 TABLE 3-9 Acceptable Concentrations of EG in Drinking Water to Prevent Adverse Effects Data/Reference Sex/Species Uncertainty Factors Acceptable Concentrations, mg/L Reference NOAEL Species Microgravity Inter-individual Exposure Time 1 d 10 d 100 d 1,000 d Kidney Minimum lethal estimate 1.6 g/kg (apply to CNS also) M/F Human 50 1 1 3 1 270 — — — Gessner et al. 1961 10-d NOAEL renal lesions, 0.5% in drinking water M/SD rats 1 10 3 3 1 — 180 — — Robinson et al. 1990 10-d BMDL10 = 520 mg/kg/d (IC) M/SD rats 1 10 3 3 1 — 140 — — Robinson et al. 1990 90-d LOAEL renal lesions, 0.25 % in drinking water M/SD rats 3 10 1 3 1.1 — — 51 — Robinson et al. 1990 90-d BMDL10 = 27 mg/kg/d (IC) M/SD rats 1 10 1 3 1.1 — — 20 4 Robinson et al. 1990 730-d NOAEL renal lesions, 0.2 g/kg/d feed M/F344 rats 1 10 1 3 1 — — — 170 DePass et al. 1986a Liver 91-d NOAEL centrilobular necrosis, 3 g/kg/d feed M/F344 rats 1 10 1 3 1.1 — — 2,300 — Melnick 1984 NTP 1993 730-d NOAEL fatty change, monocyte infil., granulomas, 0.2 g/kg/d feed F/F344 rats 1 10 1 3 1 — — — 170 DePass et al. 1986a
OCR for page 118
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Data/Reference Sex/Species Uncertainty Factors Acceptable Concentrations, mg/L Reference NOAEL Species Microgravity Inter-individual Exposure Time 1 d 10 d 100 d 1,000 d Liver 10-d NOAEL on RBC/WBC indices, 2.0% (22 g/L) drinking water F/SD rats 1 10 3 3 1 — 820 — — Robinson et al. 1990 90-d NOAEL on WBC count, 1.0% (11 g/L) drinking water F/SD rats 1 10 3 3 1.1 — 290 — Robinsonet al. 1990 730-d NOAEL RBC/WBC indices, 0.2 g/kg/d feed M/F344 rats 1 10 3 3 1 — — — 55 DePass et al. 1986a SWEG 270 140 20 4 Abbreviations: F, female; M, male; SD, Sprague-Dawley; —, not calculated.
OCR for page 119
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 REFERENCES Abbondandolo, A., S. Bonatti, C. Corsi, G. Corti, R. Fiorio, C. Leporini, A. Mazzaccaro, R. Nieri, R. Barale, and N. Loprieno. 1980. The use of organic solvents in mutagenicity testing. Mutat. Res. 79(2):141-150. ACGIH (American Conference of Governmental Industrial Hygienists). 1996. Ethylene glycol (CAS 107-21-1). In Supplements to the Sixth Edition- Documentation of Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cinncinatti, OH. Agarwal, D.P., and H.W. Goedde. 1992. Pharmacogenetics of alcohol metabolism and alcoholism. Pharmacogenetics 2(2):48-62. ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Profile for Ethylene Glycol and Propylene Glycol. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. September 1997. Bailer, A.J., R.B. Noble, and M.H. Wheeler. 2005a. Model uncertainty and risk estimation for experimental studies of quantal responses. Risk Anal. 25(2):291-299. Bailer, A.J., M. Wheeler, D. Dankovic, R. Noble, and J. Bera. 2005b. Incorporating uncertainty and variability in the assessment of occupational hazards. Int. J. Risk Assess. Manage. 5(2/3/4):344-357. Blood, F.R. 1965. Chonic toxicity of ethylene glycol in the rat. Food Cosmet. Toxicol. 3(2):229-234. Blood, F.R., G.A. Elliot, and M.S. Wright. 1962. Chronic toxicity of ethylene glycol in the monkey. Toxicol. Appl. Pharmacol. 4:489-491. Brown, C.C. 1984. High-to low-dose extrapolation in animals. Pp. 57-79 in Assessment and Management of Chemical Risks, J.V. Rodericks, and R.G. Tardiff, eds. Washington, DC: American Chemical Society. Brukner, J.V., and D.A. Warren. 2001. Toxic effects of solvents and vapors. Pp. 869-916 in Casarette and Doull’s Toxicology: The Basic Science of Poisons, 6th Ed., C.D. Klaassen, ed. New York: McGraw-Hill. Carney, E.W., N.L. Freshour, D.A. Dittenber, and M.D. Dryzga. 1999. Ethylene glycol developmental toxicity: Unraveling the roles of glycolic acid and metabolic acidosis. Toxicol. Sci. 50(1):117-126. Cavender, F.L., and E.J. Sowinski. 1994. Glycols. Pp. 4645-4719 in Patty’s Industrial Hygiene and Toxicology, Vol. 2F, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: Wiley. Chaudhuri, R.K. 1978. Effect of ethylene glycol on transcription of Neurospora crassa conidial genome. Experientia 34(6):735-736. Chung, P.K., and P. Tuso. 1989. Cerebral computed tomography in a stage IV ethylene glycol intoxication. Conn. Med. 53(9):513-514. D'Amato, F. 1948. The effect of colchicine and ethylene glycol on sticky chromosomes in Allium cepa. Hereditas 34:83-103. DePass, L.R., R.H. Garman, M.D. Woodside, W.E. Giddens, R.R. Maranpot, and C.S. Weil. 1986a. Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice. Fundam. Appl. Toxicol. 7(4):547-565. DePass, L.R., M.D. Woodside, R.R. Maronpot, and C.S. Weil. 1986b. Three-generation and dominant lethal mutagenesis studies of ethylene glycol in the rat. Fundam. Appl. Toxicol. 7(4):566-572.
OCR for page 120
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 EPA (U.S. Environmental Protection Agency). 1987. Ethylene Glycol. EPA 820-K-87-012. Health Advisory D437. Office of Drinking Water, U.S. Environmental Protection Agency. March 31, 1987. EPA (U.S. Environmental Protection Agency). 1992. Ethylene glycol (CASRN 107-21-1). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/NCEA/iris/subst/0238.htm [accessed Apr. 8, 2008]. EPA (U.S. Environmental Protection Agency). 1993. Summary of Federal and State Drinking Water Standards and Guidelines. Federal-State Toxicology and Risk Analysis Committee, Office of Water, U.S. Environmental Protection Agency, Washington, DC. November 1993. EPA (U.S. Environmental Protection Agency). 1996. Drinking Water Regulations and Health Advisories. EPA822-B-96-002. Office of Water, U.S. Environmental Protection Agency, Washington, DC. October 1996. Faustman, E.M., and G.S. Omenn. 2001. Risk assessment. Pp. 83-104 in Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th Ed., C.D. Klaassen, ed. New York: McGraw-Hill. Frantz, S.W., J.L. Beskitt, C.M. Grosse, M.J. Tallant, F.K. Dietz, and B. Ballantyne. 1996. Pharmacokinetics of ethylene glycol. II. Tissue distribution, dose-dependent elimination, and identification of urinary metabolites following single intravenous, peroral or percutaneous doses in female Sprague Dawley rats and CD-1 mice. Xenobiotica 26(11):1195-1220. Fraser, A.D., L. Coffin, and D. Worth. 2002. Drug and chemical metabolites in clinical toxicology investigations: The importance of ethylene glycol, methanol, and cannabinoid metabolite analyses. Clin. Biochem. 35(7):501-511. Garcia, H.D., and J.T. James. 2000. Furan. Pp. 307-329 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 4. Washington, DC: National Academy Press. Gershoff, S.N., and S.B. Andrus. 1962. Effect of vitamin B6 and magnesium on renal deposition of calcium oxalate induced by ethylene glycol administration. Proc. Soc. Exp. Biol. Med. 109:99-102. Gessner, P.K., D.V. Parke, and R.T. Williams. 1961. Studies in detoxication. 86. The metabolism of 14C-labelled ethylene glycol. Biochem. J. 79:482-489. Gosstandart (Russian Federation State Committee for Standardization and Metrology). 1995. Cosmonaut’s Habitable Environments On Board of Manned Spacecraft. General Medicotechnical Requirements. State Standards of the Russian Federation GOST R 50804-95. Russian Gosstandart, Moscow. Griffiths, A.J. 1979. Neurospora prototroph selection system for studying aneuploid production. Environ. Health Perspect. 31:75-80. Hanzlik, P.J., W.S. Lawrence, and G.L. Laqueur. 1947. Comparative chronic toxicity of diethylene glycol monoethyl ether (carbitol) and some related glycols: Results of continued drinking and feeding. J. Ind. Hyg. Toxicol. 29(4):233-241. Hartung, R. 1987. Dose-response relationships. Pp. 29-46 in Toxic Substances and Human Risk: Principles of Data Interpretation, R.G. Tardiff, and J.V. Rodricks, eds. New York: Plenum Press. Hewlett, T.P., D. Jacobsen, T.D. Collins, and K.E. McMartin. 1989. Ethylene glycol and glycolate kinetics in rats and dogs. Vet. Hum. Toxicol. 31(2):116-120.
OCR for page 121
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Hong, H.L., J. Canipe, C.W. Jameson, and G.A. Boorman. 1988. Comparative effects of ethylene glycol and ethylene glycol monomethyl ether exposure on hematopoiesis and histopathology in B6C3F1 mice. J. Environ. Pathol. Toxicol. Oncol. 8(Spec.7):27-38. Hunt, R. 1932. Toxicity of ethylene and propylene glycol. Ind. Eng. Chem. 24:361, 836 [as cited in Laug et al. 1939]. Huntoon, C.L., P.A. Whitson, and C.F. Sams. 1994. Hematologic and immunologic functions. Pp. 351-362 in Space Physiology and Medicine, 3rd Ed., A.E. Nicogossian, C.L. Huntoon, and S.L. Pool, eds. Philadelphia, PA: Lea and Fibiger. Jacobsen, D., T.P. Hewlett, R. Webb, S.T. Brown, A.T. Ordinario, and K.E. McMartin. 1988. Ethylene glycol intoxication: Evaluation of kinetics and crystalluria. Am. J. Med. 84(1):145-152. Kadiiska, M.B., and R.P. Mason. 2000. Ethylene glycol generates free radical metabolites in rats: An ESR in vivo spin trapping investigation. Chem. Res. Toxicol. 13(11):1187-1191. Kubinski, H., G.E. Gutzke, and Z.O. Kubinski. 1981. DNA-cell-binding (DCB) assay for suspected carcincgens and mutagens. Mutat. Res. 89(2):95-136. Kukielka, E., and A.I. Cederbaum. 1995. Increased oxidation of ethylene glycol to formaldehyde by microsomes after ethanol treatment: Role of oxygen radicals and cytochrome P-450. Toxicol. Lett. 78(1):9-15. LaKind, J.S., E.A. McKenna, R.P. Hubner, and R.G. Tardiff. 1999. A review of the comparative mammalian toxicity of ethylene glycol and propylene glycol. Crit. Rev. Toxicol. 29(4):331-365. Lamb, J.C., R.R. Maronpot, D.K. Gulati, V.S. Russell, L. Hommel-Barnes, and P.S. Sabharwal. 1985. Reproductive and developmental toxicity of ethylene glycol in the mouse. Toxicol. Appl. Pharmacol. 81(1):100-112. Laug, E.P., H.O. Calvery, H.J. Morris, and G. Woodward. 1939. The toxicology of some glycols and derivatives. J. Ind. Hyg. Toxicol. 21(5):173-201. Maguire, M.P. 1974. Chemically induced abnormal chromosome behavior at meiosis in maize. Chromosoma 48:213-223. Marshall, T.C. 1982. Dose-dependent disposition of ethylene glycol in the rat after intravenous administration. J. Toxicol. Environ. Health 10(3):397-409. McCann, J., E. Choi, E. Yamasaki, and B.N. Ames. 1975. Detection of carcinogens as mutagens in the Salmonella microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. U.S.A. 72(12):5135-5139. McChesney, E.W., L. Golberg, C.K. Parekh, and J.C. Russel. 1971. Reappraisal of the toxicity of ethylene glycol. II. Metabolism studies in laboratory animals. Food Cosmet. Toxicol. 9(1):21-38. McMartin, K.E., and T.A. Cenac. 2000. Toxicity of ethylene glycol metabolites in normal human kidney cells. Ann. N.Y. Acad. Sci. 919:315-317. Melnick, R.L. 1984. Toxicities of ethylene glycol and ethylene glycol monoethyl ether in Fischer 344/N rats and B6C3F1 mice. Environ. Health Perspect. 57:147-155. Mersch-Sundermann, V., U. Schneider, G. Klopman, and H.S. Rosenkranz. 1994. SOS induction in Eschrichia coli and Salmonella mutagenicity: A comparison using 330 compounds. Mutagenesis 9(3):205-224. Moriarty, R.W., and R.H. McDonald. 1974. The spectrum of ethylene glycol poisoning. Clin. Toxicol. 7(6):583-596. Morris, H.J., A.A. Nelson, and H.O. Calvery. 1942. Observations on the chronic toxicities of propylene glycol, ethylene glycol, diethylene glycol, ethylene glycol mono-
OCR for page 122
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 ethyl ether, and diethylene glycol monoethyl ether. J. Pharmacol. Exp. Ther. 74:266-273. Neeper-Bradley, T.L., R.W. Tyl, L.C. Fisher, M.F. Kubena, M.A. Vrbanic, and P.E. Losco. 1995. Determination of a no-observed-effect level for developmental toxicity of ethylene glycol administration by gavage to CD rats and CD-1 mice. Fundam. Appl. Toxicol. 27(1):121-130. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NTP (National Toxicology Program). 1993. Toxicology and Carcinogenesis Studies of Ethylene Glycol (CAS No. 107-21-1) in B6C3F1 Mice (Feed Studies). Technical Report No. 413. NIH Publ. No. 93-3144. U.S. Department of Health and Human Services, Public Health Services, National Institute of Health, Research Triangle Park, NC. February 1993. Parry, M.F., and R. Wallach. 1974. Ethylene glycol poisoning. Am. J. Med. 57(1):143-150. Peterson, C.D., A.J. Collins, J.M. Himes, M.L. Bullock, and W.F. Keane. 1981. Ethylene glycol poisoning: Pharmacokinetics during therapy with ethanol and hemodialysis. N. Engl. J. Med. 304(1):21-23. Pietrzyk, R.A., J.A. Jones, C.F. Sams, and P.A. Whitson. 2007. Renal stone formation among astronauts. Aviat. Space Environ. Med. 78(Suppl. 4):A9-A13. Poldelski, V., A. Johnson, S. Wright, V. Dela Rosa, and R.A. Zager. 2001. Ethylene glycol-mediated tubular injury: Identification of critical metabolites and injury pathways. Am. J. Kidney Dis. 38(2):339-348. Pottenger, L.H., E.W. Carney, and M.J. Bartels. 2001. Dose-dependent nonlinear pharmacokinetics of ethylene glycol metabolites in pregnant and nonpregnant Sprague-Dawley rats following oral administration of ethylene glycol. Toxicol. Sci. 62(1):10-19. Price, C.J., C.A. Kimmel, R.W. Tyl, and M.C. Marr. 1985. The developmental toxicity of ethylene glycol in rats and mice. Toxicol. Appl. Pharmacol. 81(1):113-127. Reif, G. 1950. Self-experiments with ethylene glycol. Pharmazie 5(6):276-278. Roberts, J.A., and H.R. Seibold. 1969. Ethylene glycol toxicity in the monkey. Toxicol. Appl. Pharmacol. 15(3):624-631. Robinson, M., C.L. Pond, R.D. Laurie, J.P. Bercz, G. Henningsen, and L.W. Condie. 1990. Subacute and subchronic toxicity of ethylene glycol administered in drinking water to Sprague-Dawley rats. Drug Chem. Toxicol. 13(1):43-70. Rofe, A.M., R. Bais, and R.A. Conyers. 1986. The effect of dietary refined sugars and sugar alcohols on renal calcium oxalate deposition in ethylene glycol-treated rats. Food Chem. Toxicol. 24(5):397-403. Rosenkranz, M., H.S. Rosenkranz, and G. Klopman. 1997. Intercellular communication, tumor promotion and non-genotoxic carcinogenesis: Relationships based upon structural considerations. Mutat. Res. 381(2):171-188. Singh, A., C. Helms, and F. Sherman. 1979. Mutation of the non-Mendelian suppressor, Ψ+, in yeast by hypertonic media. Proc. Natl. Acad. Sci. U.S.A. 76(4):1952-1956. Storer, R.D.., T.W. McKelvey, A.R. Kraynak, M.C. Elia, J.E. Barnum, L.S. Harmon, W.W. Nichols, and J.G. DeLuca. 1996. Revalidation of the in vitro alkaline elution/rat hepatocyte assay for DNA damage: Improved criteria for assessment of cytotoxicity and genotoxicity and results for 81 compounds. Mutat. Res. 368(2):59-101.
OCR for page 123
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Thomasson, H.R., D.W. Crabb, H.J. Edenberg, and T.K Li. 1993. Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism. Behav. Genet. 23(2):131-136. Tyl, R.W., C.J. Price, M.C. Marr, C.B. Myers, J.C. Seely, J.J. Heindel, and B.A. Schwetz. 1993. Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits. Fundam. Appl. Toxicol. 20(4):402-412. Tyl, RW., B. Ballantyne, L.C. Fisher, D.L. Fait, D.E. Dodd, D.R. Klonne, I.M. Pritts, and P.E. Losco. 1995a. Evaluation of the developmental toxicity of ethylene glycol aerosol in CD-1 mice by nose-only exposure. Fundam. Appl. Toxicol. 27(1):49-62. Tyl, R.W., B. Ballantyne, L.C. Fisher, D.L. Fait, T.A. Savine, D.E. Dodd, D.R. Klonne, and I.M. Pritts. 1995b. Evaluation of the developmental toxicity of ethylene glycol aerosol in CD rat and CD-1 mouse by whole-body exposure. Fundam. Appl. Toxicol. 24(1):57-75. Tyl, R.W., L.C. Fisher, M.F. Kubena, M.A. Vrbanic, and P.E. Losco. 1995c. Assessment of the developmental toxicity of ethylene glycol applied cutaneously to CD-1 mice. Fundam. Appl. Toxicol. 27(2):155-166. Walton, E.W. 1978. An epidemic of antifreeze poisoning. Med. Sci. Law 18(4):231-237. Whedon, G.D., L. Lutwak, P.C. Rambaut. M.W. Whittle, M.C. Smith, J. Reid, C. Leach, C.R. Stadler, and D.D. Sanford. 1977. Mineral and nitrogen studies, experiment M071. Pp. 164-174 in Biomedical Results from Skylab, R.S. Johnston, and L.F. Dietlein, eds. NASA SP-377, Washington, DC: National Aeronautics and Space Administration [online]. Available: http://lsda.jsc.nasa.gov/books/skylab/Ch18.htm [accessed Apr. 9, 2008]. Winek, C.L. 1975. Ethylene glycol poisoning. N. Engl. J. Med. 292(17):928-929. Winek, C.L., D.P. Shingleton, and S.P. Shanor. 1978. Ethylene and diethylene glycol toxicity. Clin. Toxicol. 13(2):297-324. Wong, K.L. 1996. Ethylene glycol. Pp. 232-270 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 3. Washington, DC: National Academy Press. Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, K. Mortelmans, and W. Speck. 1987. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ. Mutagen. 9(S9):1-110.
OCR for page 124
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 APPENDIX 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 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
OCR for page 125
Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 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