Chronic Toxicity and Oncogenicity Studies of Ethylene Glycol in Rats and Mice

DEPASS, LINVAL R.; GARMAN, ROBERT H.; WOODSIDE, MURRAY D.; GIDDENS, W. ELLIS; Maronpot, Robert R.; WEIL, CARROL S.

doi:10.1093/toxsci/7.4.547

Cited by 12 publications

(15 citation statements)

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“…Selfnitration of haemoglobin by peroxidative activity of this protein might be the reason for the presence of nitrated proteins in erythrocytes as it has been shown that in vitro exposure to peroxynitrite results in protein nitration in these cells (Denicola et al, 1998). EG poisoning has been shown to cause haemolysis (Crowell et al, 1979;DePass et al, 1986), and somehow the breakdown of haemoglobin during EG poisoning might trigger the protein nitration. Another explanation for strong immunoreactivity against nitrotyrosine antibody on erythrocytes might be release of nitric oxide from the endothelium during the intoxication and further free pass of it to these cells (Gladwin et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

Nitrosative tissue damage and apoptotic cell death in kidneys and livers of naturally ethylene glycol (antifreeze)-poisoned geese

2007

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Three naturally ethylene glycol (EG)-intoxicated geese were investigated for pathological changes, nitrosative tissue damage and apoptotic cell death. Severe degeneration of kidney tubular epithelium and congestion of kidney and liver tissues were observed. Immunohistochemical staining for inducible nitric oxide synthase and nitrotyrosine revealed strong immunoreactivity with both antibodies in kidney and liver tissues compared with the weak immunostaining in the control animals. In both tissues of the EG-intoxicated geese, erythrocytes were also highly immunoreactive with nitrotyrosine antibody. A high degree of apoptotic cell death was present in the kidney tubule epithelium of EG-intoxicated geese. Some apoptotic cells were also observed in the liver. These results show that nitrosative tissue damage and apoptotic cell death takes place in kidney and liver during EG intoxication in geese.

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Section: Resultsmentioning

confidence: 99%

Nitrosative tissue damage and apoptotic cell death in kidneys and livers of naturally ethylene glycol (antifreeze)-poisoned geese

2007

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“…Thus crystalluria, identified by simple microscopy of the urine, is an important and rather specific diagnostic tool and repeated urinalysis is very useful in the differential diagnosis of an anion gap metabolic acidosis of unknown origin (Jacobsen et al 1988). In experimental animals, EG-associated renal damage has been observed only at doses greater than those at which there were increases in crystalluria (DePass et al 1986). …”

Section: Mode Of Action Of Renal Effectsmentioning

confidence: 99%

“…In relevant studies quoted in the CICAD (2002) document, the no observed adverse effect level (NOAEL) for renal effects of EG in the most sensitive animal species (male rat) was determined to be a daily oral dose of 200 mg/kg in a pivotal chronic 2-year bioassay (DePass et al 1986). In a subchronic 13-week study the NOAEL corresponded to an approximate daily intake of 400 mg/kg (Robinson et al 1990).…”

Section: Dose Responsementioning

confidence: 99%

“…This appears to be feasible on the basis of renal effects that were typically observed in rats. In a 2-year bioassay a daily oral dose of 200 mg/kg has been determined as the NOAEL (DePass et al 1986). In the CICAD (2002) document a tolerable intake for EG, with regard to the development of histopathological changes in the kidney of male rats, has been derived from Gaunt et al (1974) based on a benchmark dose 05 (BMD 05, the dose estimated to cause a 5% increase in incidence over the background response rate, calculated according to Howe 1995).…”

Section: Dose Responsementioning

confidence: 99%

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Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data

2004

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Upon ingestion ethylene glycol (EG, monoethylene glycol) is rapidly absorbed from the gastrointestinal tract, and depending on the severity of exposure signs of toxicity may progress through three stages. Neurological effects characterize the first step consisting of central nervous depression (intoxication, lethargy, seizures, and coma). The second stage, usually 12-24 h after ingestion, is characterized by metabolic acidosis due to the accumulation of acidic metabolites of EG, primarily glycolic acid (GA), contributing to the ensuing osmolal and anion gaps. Stage 3, generally 24-72 h after ingestion, is determined mainly by oxalic acid excretion, nephropathy, and eventual renal failure. Because the toxicity of EG is mediated principally through its metabolites, adequate analytical methods are essential to provide the information necessary for diagnosis and therapeutic management. The severe metabolic acidosis and multiple organ failure caused by ingestion of high doses of EG is a medical emergency that usually requires immediate measures to support respiration, correct the electrolyte imbalance, and initiate hemodialysis. Since metabolic acidosis is not specific to EG, whenever EG intoxication is suspected, every effort should be made to determine EG as well as its major metabolite GA in plasma to confirm the diagnosis and to institute special treatment without delay. A number of specific and sensitive analytical methods (GC, GC-MS, or HPLC) are available for this purpose. Due to the rapid metabolism of EG, the plasma concentration of GA may be higher than that of EG already upon admission. As toxicity is largely a consequence of metabolism of EG to GA and oxalic acid, the simultaneous quantification of EG and GA is important. Formation of calcium oxalate monohydrate in the urine may be a useful indicator of developing oxalate nephrosis although urine crystals can result without renal injury. The pathways involved in the metabolism of EG are qualitatively similar in humans and laboratory animals, although quantitative differences have been reported. Comparison between species is difficult, however, because the information on humans is derived mainly from acute poisoning cases whereas the effects of repeated exposures have been investigated in animal experiments. Based on published data the minimum human lethal dose of EG has been estimated at approx. 100 ml for a 70-kg adult or 1.6 g/kg body weight (calculation of dose in ml/kg to mg/kg based in EG density=1.11 g/l). However, human data from case reports are generally insufficient for the determination of a clear dose-response relationship and quantification of threshold doses for systemic toxicity, in particular renal effects, is limited. As toxicity is largely a consequence of metabolism of EG to GA, it is important to note that no signs of renal injury have developed at initial plasma glycolate concentrations of up to 10.1 mM (76.7 mg/dl). Plasma EG levels of 3.2 mM (20 mg/dl) are considered the threshold of toxicity for systemic exposure, if thera...

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“…Embryotoxicity in EG-and GA-treated rats was related to GA (Carney et al 1999). In rats, receiving EG in their food over 2 years, no-observed-effect-levels (NOELs) for EG-induced nephrotoxicity were 0.2% in food [about 80 mg/kg body weight (bw) per day for 2 years; Blood 1965] and 0.5% (about 200 mg/kg bw per day for 2 years; DePass et al 1986). For B6C3F1 mice, the corresponding NOEL was 0.6% in food (about 1500 mg/kg bw per day for 2 years; National Toxicology Program 1993, cited in LaKind et al 1999.…”

Section: Introductionmentioning

confidence: 99%

Human inhalation exposure to ethylene glycol

Carstens

Csanády²,

Faller

et al. 2003

Archives of Toxicology

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Two male volunteers (A and B) inhaled 1.43 and 1.34 mmol, respectively, of vaporous (13)C-labeled ethylene glycol ((13)C(2)-EG) over 4 h. In plasma, (13)C(2)-EG and its metabolite (13)C(2)-glycolic acid ((13)C(2)-GA) were determined together with the natural burden from background GA using a gas chromatograph equipped with a mass selective detector. Maximum plasma concentrations of (13)C(2)-EG were 11.0 and 15.8 micromol/l, and of (13)C(2)-GA were 0.9 and 1.8 micromol/l, for volunteers A and B, respectively. Corresponding plasma half-lives were 2.1 and 2.6 h for (13)C(2)-EG, and 2.9 and 2.6 h for (13)C(2)-GA. Background GA concentrations were 25.8 and 28.3 micro mol/l plasma. Unlabeled background EG, GA and oxalic acid (OA) were detected in urine in which the corresponding (13)C-labeled compounds were also quantified. Within 28 h after the start of the exposures, 6.4% and 9.3% (13)C(2)-EG, 0.70% and 0.92% (13)C(2)-GA, as well as 0.08% and 0.28% (13)C(2)-OA of the inhaled amounts of (13)C(2)-EG, were excreted in urine by volunteers A and B, respectively. The amounts of (13)C(2)-GA represented 3.7% and 14.2% of background urinary GA excreted over 24 h (274 and 88 micromol). The amounts of (13)C(2)-OA were 0.5% and 2.1% of background urinary OA excreted over 24 h (215 and 177 micromol). From the findings obtained in plasma and urine and from a toxicokinetic analysis of these data, it is highly unlikely that workplace EG exposure according to the German exposure limit (MAK-value 10 ppm EG, 8 h) could lead to adverse effects from the metabolically formed GA and OA.

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Chronic Toxicity and Oncogenicity Studies of Ethylene Glycol in Rats and Mice

Cited by 12 publications

References 0 publications

Nitrosative tissue damage and apoptotic cell death in kidneys and livers of naturally ethylene glycol (antifreeze)-poisoned geese

Nitrosative tissue damage and apoptotic cell death in kidneys and livers of naturally ethylene glycol (antifreeze)-poisoned geese

Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data

Human inhalation exposure to ethylene glycol

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