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Ethylene glycol (EG), in addition to its neurotoxic and nephrotoxic effects, evokes oxidative stress. The aim of this study was to assess the influence of the ethylene glycol on the biochemical indicators and oxidoreductive balance of patients treated for acute poisoning. The total study group consisted of 56 persons including 26 alcoholics who took EG as a substitute for ethyl alcohol in the course of alcohol dependence syndrome and 30 controls. Severity of poisoning, results of acid-base parameters, biochemical, and toxicological tests as well as biomarkers of the oxidative stress in blood were analyzed during the patients' hospitalization. The key issue was to assess the oxidative stress and biochemical disturbances caused by EG and the type of treatment applied in the course of poisoning. Significant changes in some parameters were found both at time of diagnosis and after treatment initiation (ethanol as an antidote and hemodialysis). The most important differences included the activity of hepatic parameters (aspartate aminotransferase, AST) and oxidative stress markers like catalase (CAT); correlation of the lipid peroxidation products level (TBARS) with urea concentration has been shown. On the last day of the hospitalization, in some cases, the mutual correlation between the evaluated markers were observed, for example, between alanine transaminase (ALT) and glutathione reductase (GR), and urea concentration and glutathione level (GSH/GSSG). The concentration of ions (H + ) had a major impact on the oxidoreductive balance, correlating with the elevated GR and GSH/GSSG levels.

Context: Diethylene glycol (DEG) is an organic compound found in household products but also as an adulterant in medicines by acting as a counterfeit solvent. DEG poisonings have been characterized predominately by acute kidney injury (AKI), but also by delayed neurological sequelae such as decreased reflexes or face and limb weakness., Objectives: Characterizing the neurological symptoms of DEG poisoning in a subacute animal model would create a clearer picture of overall toxicity and possibly make mechanistic connections between kidney injury and neuropathy., Methods: Male Wistar-Han rats were orally administered doses of 4 - 6 g/kg DEG every 12 or 24 h and monitored for 7 days. Urine was collected every 12 h and endpoint blood and cerebrospinal fluid (CSF) were collected for a renal plasma panel and total protein estimation, respectively. Motor function tests were conducted before and after treatment. Kidney and brain tissue was harvested for metabolic analysis., Results: Of the 43 animals treated with DEG, 11 developed AKI as confirmed by increased BUN and creatinine levels. Renal and brain DGA accumulation was markedly increased in animals that developed AKI compared to animals without AKI. The total protein content in CSF in animals with kidney injury was markedly elevated compared to control and to treated animals without AKI. Significant decreases in forelimb grip strength and decreases in locomotor and rearing activity were observed in animals with AKI compared to control and to animals without AKI., Discussion: Repeated dosing with DEG in an animal model produced nephrotoxic effects like those in studies with acute DEG administration. The decrease in motor function and increase in CSF protein were only present in animals that developed AKI., Conclusions: These studies show development of neurotoxicity in this DEG animal model and suggest that neurological symptoms are observed only when DGA accumulation and kidney injury also occur.

Ingestion of toxic alcohols (TA) typically presents with a high anion gap (AG) metabolic acidosis, and elevated osmolar gap (OG). Hemodialysis (HD) has not been recommended in early phases of intoxication with high OG and normal AG metabolic acidosis. We describe the case of a 40-year-old male who was brought to our emergency department for reported paint thinner ingestion. He was unable to protect his airway and required intubation. Blood gas showed respiratory acidosis, an initial AG, corrected by albumin of 12.75, lactic acid 5.26 mmol/L, and an OG of 170. Patient was treated with bicarbonate drip, fomepizole and emergent HD, which improved his neurologic status. Days after his admission, alcohol levels came positive for a co-ingestion of ethylene glycol, diethylene glycol, and methanol. Most of the TA are metabolized into their toxic byproducts by the enzyme alcohol dehydrogenase (ADH). The kinetics of these alcohols will be altered when there is co-ingestion of multiple substances. Moreover, early ingestions will translate in a high OG without a high AG. False elevation of lactate can occur with the ingestion of ethylene glycol due to a cross-reaction with L-lactate oxidase in the analyzer. In our case, the administration of fomepizole followed by an early HD given the poor clinical improvement, was followed by a fast recovery of the neurological status and potentially prevented renal failure. A high index of suspicion for TA ingestion should be raised when encountering an individual with lactic acidosis, high OG, and normal AG.

Objective: To determine whether trace amounts of ethylene glycol (EG), diethylene glycol (DEG), or triethylene glycol (TEG) in PEG 3350 are associated with increased blood levels of EG, DEG, or TEG in children receiving daily PEG 3350 therapy., Study Design: Blood samples were drawn from 9 children who were being treated for constipation with PEG 3350 (6-12 years old) before and every 30 minutes for 3 hours after receiving 17 g of PEG 3350. PEG 3350, tap water, and blood samples from 18 age- and sex-matched controls also were analyzed., Results: Baseline blood levels of EG and TEG did not differ between control and treated groups. DEG levels (median [IQR]) were lower in the PEG 3350 group (40.13 ng/mL [36.69, 63.94] vs 92.83 ng/mL [51.06, 128.93], P = .008). After PEG 3350 dose, levels of EG (390.51 ng/mL [326.06, 624.55]) and TEG (2.21 ng/mL [0, 4.5]) peaked at 90 minutes at 1032.81 ng/mL (826.84, 1486.13) (P = .009) and 35.17 ng/mL (15.81, 45.13) (P = .0005), respectively. DEG levels did not significantly change. Standard 17-g doses of PEG 3350 in 8 oz (237 mL) of water resulted in concentrations (mean ± SD) of EG, DEG, and TEG of 1.32 ± 0.23 µg/mL, 0.18 ± 0.03 µg/mL, and 0.12 ± 0.01 µg/mL, respectively. EG, DEG, and TEG levels in public water supply were 0.07 µg/mL, 0.21 µg/mL, and 0.02 µg/mL, respectively., Conclusions: Daily PEG 3350 therapy in children was not associated with sustained elevation of EG, DEG, or TEG blood levels over levels in matched controls. Although EG and TEG levels increased after a standard dose of PEG 3350, their peak values remained well below toxic levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: A growing body of evidence suggests that cardiovascular disease risk factors including hypertension may be linked to sporadic Alzheimer's disease (AD). It is well known that hypertension is associated with cerebrovascular disease and vascular dementia on the basis of vascular remodeling. However, the mechanisms linking hypertension and AD remain unclear., Methods: We studied 197 patients with AD (86 male; mean age ± SD: 75.8 ± 7.4 years) from the Alzheimer's Disease Neuroimaging Initiative database with (n = 97) and without (n = 100) hypertension. We explored associations between hypertension and clinical, plasma, cerebrospinal fluid and imaging markers of AD pathology in order to elucidate the underlying mechanisms that may link AD and hypertension., Results: We found that patients with AD with hypertension had worse cognitive function (Alzheimer's disease Assessment Scale-cognitive subscale, P = 0.038) and higher neuropsychiatric symptom burden (Neuropsychiatric Inventory Questionnaire, P = 0.016) compared with those without hypertension. Patients with AD with hypertension showed reduced glucose hypometabolism in the right (P < 0.001) and left (P = 0.007) hippocampus. No differences were found in magnetic resonance imaging volumetric measurements, [ 18 F]florbetapir uptakes, plasma and cerebrospinal fluid between patients with AD with and without hypertension., Conclusions: Although hypertension is associated with worse cognitive function, behavioural symptoms and hippocampal glucose hypometabolism, it is not associated with evidence of increased amyloid or tau pathology. Effective management of hypertension may potentially have a therapeutic role in the alleviation of symptoms in AD., (© 2017 EAN.)

Alcohol ethoxylates (AEs) are a major class of non-ionic surfactants, which are widely used in household, institutional and industrial cleaners, and they are considered as an alternative of nonylphenol. In this study, a rapid, sensitive and reliable bioanalytical method was developed for the determination of octaethylene glycol monodecyl ether (C10E8, an AE) in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Chromatographic separation was performed on a reversed-phase C18 column (2.1 mm × 50 mm, 2.1 μm). The mobile phase consisted of 0.1% formic acid in distilled water and 0.1% formic acid in acetonitrile (40:60% v/v). The flow rate was 0.3 mL/min. For mass spectrometric detection, the multiple reaction monitoring (MRM) mode was used; the MRM transitions were m/z 511.5 → m/z 133.1 for C10E8 and m/z 423.3 → m/z 133.1 for hexaethylene glycol monodecyl ether (internal standard) in the positive ion mode. A calibration curve was constructed within the range of 2-2,000 ng/mL; the intra- (n = 5) and inter-day (n = 3) precision and accuracy were within 10%. The LC-MS-MS method was specific, accurate and reproducible, and this method was successfully applied in a pharmacokinetic study of C10E8 in rats. C10E8 was intravenously (1 mg/kg, n = 6) and orally (10 mg/kg, n = 7) administered to rats. The kinetic parameters were analyzed based on a noncompartmental statistical model using the pharmacokinetic modeling software (WinNonlin). The oral bioavailability of C10E8 was 34.4%., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: We present a 5-year review of our UK service for plasma ethylene glycol and diethylene glycol determination in cases of acute poisoning., Methods: Ethylene glycol and diethylene glycol have been measured on all samples received for screening for toxicity by gas chromatography-flame ionization detection over a five-year period. A detailed audit of the results has been undertaken., Results: In this period, we received 811 requests, 56% were for first-time screening and 44% repeat analysis where a positive sample has already been received. Of the first-time screen samples, 33.5% screened positive for glycol poisoning. The mean positive ethylene glycol concentration was 1204 mg/L (range 31 to 8666 mg/L). Diethylene glycol was present in 14% of ethylene glycol positive samples but never found alone., Conclusions: The data presented here suggest it is not essential to measure diethylene glycol since its inclusion is rarely likely to change patient management., (© The Author(s) 2015.)

Objective: To evaluate the effects of handling alone versus handling under anaesthesia with 2-phenoxyethanol or etomidate on haematological parameters in carp., Study Design: Prospective, randomized, laboratory experiment., Animals: Seventy-two juvenile carp (Cyprinus carpio) weighing 35.9 ± 10.4 g were divided into six groups of 12 fish., Methods: Either 2-phenoxyethanol or 2% etomidate were administered to induce deep anaesthesia (0.3 mL L(-1) and 0.6 mL L(-1) , respectively) or deep sedation (0.15 mL L(-1) and 0.3 mL L(-1) , respectively). Fish were handled with and without sedation. Blood was sampled at 1 hour and 1 week post-treatment. Phagocyte oxidative activity [nitrotetrazolium blue reduction test (NBT)] and differential erythrocyte [red blood cell (RBC)] and leukocyte (white blood cell) counts were evaluated., Results: At 1 hour after the induction of anaesthesia, haematocrit (Ht) and haemoglobin (Hb) were increased in fish anaesthetized with 2-phenoxyethanol, and mean corpuscular haemoglobin (MCH) was increased in fish anaesthetized with etomidate. At 1 week, an increase in RBC, erythroblastosis, erythrocyte damage, lymphopenia, neutrophilia, monocytosis and thrombocytosis occurred in both groups. Red blood parameters did not change 1 hour after handling alone, but after 1 week Ht, Hb and mean cell volume decreased, whereas MCH concentration (MCHC) and abnormal erythrocytes increased. Lymphopenia, neutrophilia, monocytosis, thrombocytosis and a decrease in NBT occurred. Fish handled under sedation showed an increase in Hb and MCHC followed by a decrease at 1 week in Ht, Hb and MCH, erythroblastosis and increased abnormal erythrocytes. Lymphopenia and neutrophilia were less pronounced than in fish handled without sedation, but a decrease in NBT was noted at 1 week post-treatment., Conclusions and Clinical Relevance: Deep anaesthesia with 2-phenoxyethanol or etomidate induced significant haematological alterations in juvenile carp. Deep sedation reduced the immediate immunosuppressive effects of handling but did not eliminate longterm effects. These anaesthetics should be avoided during experimental procedures involving haematological measurements. In contexts that require the short-term handling of carp, these drugs should be used with caution in view of their possible side effects., (© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10g/kg DEG and blood, kidney and liver tissues were collected at 48h. Both rat strains treated with 10g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10g/kg DEG, but no DGA was present at 2 or 5g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments., Competing Interests: statement The authors declare that there are no conflicts of interest., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Context: Methanol, ethylene glycol, diethylene glycol, and propylene glycol intoxications are associated with cellular dysfunction and an increased risk of death. Adverse effects can develop quickly; thus, there is a need for methods for rapidly detecting their presence., Objective: To examine the value and limitations of present methods to diagnose patients with possible toxic alcohol exposure., Methods: I searched MEDLINE for articles published between 1969 and 2014 using the terms: toxic alcohols, serum osmolality, serum osmol gap, serum anion gap, metabolic acidosis, methanol, ethylene glycol, diethylene glycol, propylene glycol, and fomepizole. Each article was reviewed for additional references., Results: The diagnosis of toxic alcohol exposure is often made on the basis of this history and physical findings along with an increase in the serum osmol and anion gaps. However, an increase in the osmol and/or anion gaps is not always present. Definitive detection in blood requires gas or liquid chromatography, laborious and expensive procedures which are not always available. Newer methods including a qualitative colorimetric test for detection of all alcohols or enzymatic tests for a specific alcohol might allow for more rapid diagnosis., Conclusions: Exposure to toxic alcohols is associated with cellular dysfunction and increased risk of death. Treatment, if initiated early, can markedly improve outcome, but present methods of diagnosis including changes in serum osmol and anion gap, and use of gas or liquid chromatography have important limitations. Development of more rapid and effective tests for detection of these intoxications is essential for optimal care of patients.

A liquid chromatography coupled with electrospray tandem mass spectrometry method was developed for the analysis of ethylene glycol, diethylene glycol, triethylene glycol, 1,4-butanediol, 1,2-butanediol, 2,3-butanediol, 1,2-propanediol and 1,3-propanediol, in serum after a Schotten-Baumann derivatization by benzoyl chloride. Usual validation parameters were tested: linearity, repeatability and intermediate precision, limits of detection and quantification, carry over and ion suppression. Limits of detection were between 0.18 and 1.1 mg/L, and limits of quantification were between 0.4 and 2.3 mg/L. Separation of isomers was possible either chromatographically or by selecting specific multiple reaction monitoring transitions. This method could be a useful tool in case of suspected intoxication with antifreeze agents, solvents, dietary supplements or some medical drug compounds., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as fomepizole and/or hemodialysis would be much stronger., Objective: To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study., Methods: In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured in serum, urine, and CSF: DEG, 2-hydroxyethoxyacetic acid (HEAA), diglycolic acid, ethylene glycol, glycolic acid, and oxalic acid. Analytes were measured using low resolution GC/MS, descriptive statistics calculated and case results compared with controls when appropriate. Specimens were de-identified so previously collected demographic, exposure, and health data were not available. The Wilcoxon Rank Sum test (with exact p-values) and bivariable exact logistic regression were used in SAS v9.2 for data analysis., Results: The following samples were analyzed: serum, 20 case, and 20 controls; urine, 11 case and 22 controls; and CSF, 11 samples from 10 cases and no controls. Diglycolic acid was detected in all case serum samples (median, 40.7 mcg/mL; range, 22.6-75.2) and no controls, and in all case urine samples (median, 28.7 mcg/mL; range, 14-118.4) and only five (23%) controls (median, < Lower Limit of Quantitation (LLQ); range, < LLQ-43.3 mcg/mL). Significant differences and associations were identified between case status and the following: 1) serum oxalic acid and serum HEAA (both OR = 14.6; 95% C I = 2.8-100.9); 2) serum diglycolic acid and urine diglycolic acid (both OR > 999; exact p < 0.0001); and 3) urinary glycolic acid (OR = 0.057; 95% C I = 0.001-0.55). Two CSF sample results were excluded and two from the same case were averaged, yielding eight samples from eight cases. Diglycolic acid was detected in seven (88%) of case CSF samples (median, 2.03 mcg/mL; range, < LLQ, 7.47)., Discussion: Significantly elevated HEAA (serum) and diglycolic acid (serum and urine) concentrations were identified among cases, which is consistent with animal data. Low urinary glycolic acid concentrations in cases may have been due to concurrent AKI. Although serum glycolic concentrations among cases may have initially increased, further metabolism to oxalic acid may have occurred thereby explaining the similar glycolic acid concentrations in cases and controls. The increased serum oxalic acid concentration results in cases versus controls are consistent with this hypothesis., Conclusion: Diglycolic acid is associated with human DEG poisoning and may be a biomarker for poisoning. These findings add to animal data suggesting a possible role for traditional antidotal therapies. The detection of HEAA and diglycolic acid in the CSF of cases suggests a possible association with signs and symptoms of DEG-associated neurotoxicity. Further work characterizing the pathophysiology of DEG-associated neurotoxicity and the role of traditional toxic alcohol therapies such as fomepizole and hemodialysis is needed.

An ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method was developed and validated to determine AV-45 in rat plasma. After the addition of the internal standard benzophenone, plasma samples were pretreated by protein precipitation. Chromatographic separation was achieved on an Acquity UPLC BEH C₁₈ column (50 × 2.1 mm, 1.7 µm) by gradient elution at a flow rate of 0.4 mL/min. Detection of analytes and internal standard (IS) was done by tandem mass spectrometry, operating in positive-ion and multiple reaction monitoring mode. The method was fully validated for its sensitivity, selectivity, accuracy and precision, matrix effect and stability study. The calibration curve showed good linearity over the concentration range 2.00-1000 ng/mL for AV-45. Intra- and inter-day precisions were less than 7.6%, and accuracy ranged from 100.6 to 107.8%. There was no matrix effect. The validated method was successfully applied to a pharmacokinetic study of AV-45 in rats. Additionally, the metabolism of AV-45 in rat liver microsomes was also studied by ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC/TOF-MS). With the help of chromatographic behavior and accurate mass measurements, the metabolites were characterized., (Copyright © 2011 John Wiley & Sons, Ltd.)

The poly(epsilon-caprolactone)-co-poly(ethylene glycol) (PCL-MPEG) amphiphilic diblock copolymer with molar ratio of epsilon-CL to MPEG 81:1 is synthesized via a ring-opening polymerization without a catalyst. The M(w) and M(n) molecular weights and the polydispersities are 18,000, 11,000 g/mole and 1.55, respectively. The pegylated amphiphilic copolymer forms micelles with a low critical micelle concentration 6.71 x 10(-8) mole/L, and the average particle size of copolymeric micelles is 62.3 +/- 12.9 nm. The degradation behavior of diblock copolymer was studied in rat plasma at 37 degrees C for 90 days. The changes of mass, composition, morphology, molecular weight, and thermal property of PCL-MPEG copolymer were investigated. The decrease of copolymer mass shows two phases with rate constants of 1.91 x 10(-1) day(-1) in the first-phase (1-24 h) and 1.77 x 10(-3) day(-1) in the second-phase (1-90 days). The degradation of labile ester linkage between PCL block and MPEG block accounts for continuous decrease of copolymer mass in plasma. The decrease of EG molar ratio from 1.30 to 0.67 and prominent reduction of enthalpy of fusion of remained copolymer from 116.5 to 85.2 J/g provide evidences of PCL-MPEG chain scission. On the other hand, the presence of partially degraded copolymers in the residuals results in its polydispersity increased from 1.55 to 2.24 at the end of 90 days. Nevertheless, the surface erosion of copolymer makes the molecular weight not quite different from its original value., (Copyright 2007 Wiley Periodicals, Inc.)

The ability of tetraethylene glycol dimethyl ether (tetraglyme) plasma deposited coatings exhibiting ultralow fibrinogen adsorption to reduce blood activation was studied with six in vitro methods, namely fibrinogen and von Willebrand's factor adsorption, total protein adsorption, clotting time in recalcified plasma, platelet adhesion and procoagulant activity, and whole blood thrombosis in a disturbed flow catheter model. Surface plasmon resonance results showed that tetraglyme surfaces strongly resisted the adsorption of all proteins from human plasma. The clotting time in the presence of tetraglyme surfaces was lengthened compared with controls, indicating a lower activation of the intrinsic coagulation cascade. Platelet adhesion and thrombin generation by adherent platelets were greatly reduced on tetraglyme-coated materials, compared with uncoated and Biospan-coated glass slides. In the in vitro disturbed blood flow model, tetraglyme plasma coated catheters had 50% less thrombus than did the uncoated catheters. Tetraglyme-coated materials thus had greatly reduced blood interactions as measured with all six methods. The improved blood compatibility of plasma-deposited tetraglyme is thus not only due to their reduced platelet adhesion and activation, but also to a generalized reduction in blood interactions., ((c) 2007 Wiley Periodicals, Inc.)

Rapid and reliable methods for identification of chlorhexidine (CHD) and nonylphenolethoxylates (NPEOn) in antiseptic and hemolyzed blood using electrospray ionization mass spectrometry (ESI-MS) were developed. Fragmental analysis provides accurate evidence for the presence of CHD in the samples. For the determination of CHD in hemolyzed blood, the method was also developed using LC-ESI-MS. Linearity of calibration curve was obtained over the concentration range of 0.1-11 microg/mL with residuals from -4.3 to 6.7%. We applied the methods to the case of suicidal injection of antiseptic and successfully detected CHD and NPEOn from hemolyzed blood. The CHD concentration was 352 microg/mL.

Background: Obtaining a precise diagnosis in patients presenting with metabolic acidosis of unknown origin is difficult. Poisoning with methanol or ethylene glycol should be suspected in cases with a combined increase of osmolal and anion gaps., Materials and Methods: Retrospectively we have compared the methanol and ethylene glycol values in poisoned patients with their osmolal gaps. The anion gaps are compared to the toxic anions measured., Results: There were good correlations between serum alcohols and osmolal gaps and between toxic metabolites and anion gaps., Interpretation: The osmolal and the anion gaps are both helpful tools in the diagnosis of patients with metabolic acidosis of unknown origin, especially for identifying patients poisoned with methanol or ethylene glycol.

Objectives: To study the influence of the presence of water on the dermal absorption of 2-butoxyethanol (BE) in volunteers., Methods: Six male volunteers were dermally exposed to 50%, 90% or neat w/w BE for 4 h on the volar forearm over an area of 40 cm(2). An inhalation exposure with a known input rate and duration served as a reference dosage. The dermal absorption parameters were calculated from 24-h excretion of total (free + conjugated) butoxyacetic acid (BAA) in urine and BE in blood, measured after both inhalation and dermal exposure., Results: The dermal absorption of BE from aqueous solutions was markedly higher than that of neat BE. The time-weighted average dermal fluxes were calculated from the urine and blood data and expressed in milligrammes per square centimetre per hour. The dermal fluxes obtained from cumulative 24-h excretion of BAA amounted to 1.34+/-0.49, 0.92+/-0.60 and 0.26+/-0.17 mg cm(-2) h(-1 )for 50%, 90% and neat BE, respectively. The dermal fluxes calculated from the BE blood data amounted to 0.92+/-0.34 and 0.74+/-0.25 mg cm(-2) h(-1 )for 50% and 90% BE, respectively. The permeation rates into the blood reached a plateau between 60 and 120 min after the start of exposure, indicating achievement of steady-state permeation. The apparent permeability coefficient K(p), was 1.75+/-0.53x10(-3) and 0.88+/-0.42x10(-3) cm h(-1 )for 50% and 90% BE, respectively., Conclusion: The percutaneous absorption of BE from aqueous solution increased markedly when compared with neat BE. Even water content as low as 10% led to an approximate fourfold increase in the permeation rates. These findings are important for the health risk assessment of occupational exposure to BE, since BE is commonly used in mixtures that contain water. Exposure to aqueous solutions of 50% and 90% of BE may result in substantial skin absorption: if a 60-min skin contact of 1,000 cm(2) is assumed, dermal uptake would be four-times higher than the pulmonary uptake of an 8-h occupational exposure at a TLV of 100 mg m(-3). This clearly justifies the skin notation for BE. For the purpose of biological monitoring, both BE in blood and BAA in urine were shown to be reliable indicators of exposure.

In this paper the authors presented the group 2-ethoxyethanol intoxication of 8 young men aged between 20 to 22. 50-100 ml of pure compound (diluted with water) was administrated as a drink. In this paper symptoms of acute intoxication to this compound were presented. GC-FID and GC-MS were used as diagnostic tools. The obtained results were compared with the data from available literature.

A gas chromatographic-mass spectrometric assay is described for identification and quantification of the antifreezes ethylene glycol (EG) and diethylene glycol (DEG) in plasma for early diagnosis of a glycol intoxication. After addition of 1,3-propanediol as internal standard, the plasma sample was deproteinized by acetone and an aliquot of the supernatant was evaporated followed by microwave-assisted pivalylation. After gas chromatographic separation, the glycols were first identified by comparison of the full mass spectra with reference spectra and then quantified. The quantification has been validated according to the criteria established by the Journal of Chromatography B. The assay was found to be selective. The calibration curves for EG and DEG were linear from 0.1 g/l to 1.0 g/l. The limit of detection for EG and DEG was 0.01 g/l and the limit of quantification for both was 0.1 g/l. The absolute recoveries were 50 and 65% for the low quality control samples and 51 and 73% for the high quality control samples of EG and DEG, respectively. Intra- and inter-day accuracy and precision were inside the required limits. The glycols in frozen plasma samples were stable for more than 6 months. The method was successfully applied to several authentic plasma samples from patients intoxicated with glycols. It has also been suitable for analysis of EG and DEG in urine.

Determination of toxic glycols and alcohols in an emergency setting requires a rapid yet accurate and reliable method. To simultaneously determine diethylene glycol (DEG) along with ethylene glycol, methanol, isopropanol, acetone, and ethanol, we modified a previously developed gas chromatographic (GC) method. The system used a Hewlett-Packard 6890 GC with EPC, a Gooseneck splitless liner, and an Rtx-200 capillary column (30 m x 0.53-mm i.d., 3 mm). After serum samples were deproteinized using ultrafiltration (Millipore Ultrafree-MC), 1 mL of the protein-free filtrate was manually injected into the GC. Internal standards for alcohols (and acetone) and glycols were n-propanol and 1,3-butanediol, respectively. All compounds eluted within 3.5 min (linear temperature gradient from 40 to 260 degrees C); total run time was 6.5 min. Limit of detection and linear range for all compounds were 1 or 2.5 mg/dL and 0-500 mg/dL, respectively. In addition, there was no interference from propionic acid, propylene glycol, and 2,3-butanediol. The modifications in the equipment and temperature program allowed increased resolution and thus, detection and reliable quantitation of DEG and other common toxic glycols and alcohols of clinical interest.

Objectives: To investigate the effects of ethylene glycol monomethyl ether (EGME) on haematology and reproduction in exposed workers., Methods: 53 Impregnation workers from two factories that make copper clad laminate with EGME as a solvent were recruited as the exposed group. Another group of 121 lamination workers with indirect exposure to EGME was recruited as the control group. Environmental monitoring of concentrations of EGME in air and biological monitoring of urinary methoxyacetic acid (MAA) concentrations were performed. Venous blood was collected for routine and biochemical analyses. Semen was collected from 14 workers exposed to EGME for sperm analysis and was compared with 13 control workers., Results: Results of haematological examination showed that the haemoglobin, packed cell volume, and red blood cell count in the male workers exposed to EGME were significantly lower than in the controls. The frequency of anaemia in the exposed group (26.1%) was significantly higher than in the control group (3.2%). However, no differences were found between the female workers exposed and not exposed to EGME. After adjustment for sex, body mass index, and duration of employment, red blood cell count was significantly negatively associated with air concentrations of EGME, and haemoglobin, packed cell volume, and red blood cell count were significantly negatively associated with urinary concentrations of MAA. The pH of semen in the exposed workers was significantly lower than in the control workers, but there were no significant differences in the sperm count or sperm morphology between the exposed and control groups., Conclusion: It can be concluded that EGME is a haematological toxin, which leads to anaemia in the exposed workers. However, the data from this study did not support the theory of a spermatotoxic effect of EGME.

Background: Severe toxic ingestions of butoxyethanol (CAS No. 111-76-2) are rare despite the prevalence of this glycol ether in products such as glass and surface cleaners. Manifestations of acute butoxyethanol toxicity include metabolic acidosis, hemolysis, hepatorenal dysfunction, and coma, but vary widely in reported cases. Furthermore, the optimal therapeutic approach is not yet established. Much of the toxicity of butoxyethanol has been ascribed to its aldehyde and acid metabolites which are similar to those produced by oxidative metabolism of methanol and ethylene glycol. Although the roles of alcohol dehydrogenase inhibition with ethanol or fomepizole and hemodialysis are clear in the case of toxic ingestions of methanol and ethylene glycol, they remain poorly defined for butoxyethanol poisoning., Case Report: We report the case of a 51-year-old female who ingested up to 8 ounces of Sanford Expo White Board Cleaner (butoxyethanol and isopropanol). She developed prolonged hyperchloremic metabolic acidosis and mental status depression and was treated with ethanol therapy but not hemodialysis. This patient recovered without apparent sequelae. The kinetics of butoxyethanol metabolism in this case are described and the potential therapeutic options are discussed.

2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and solvents. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is believed to be responsible for 2BE toxicities associated with hemolysis of red blood cells. The objective of the study was to characterize the systemic disposition of 2BE and 2BAA in rats and mice during 2-year 2BE inhalation toxicity studies. Male and female F344 rats and B6C3F1 mice (6-7 weeks old) were exposed to target 2BE concentrations of 0, 31.2, 62.5, or 125 ppm (rats), or 0, 62.5, 125, or 250 ppm (mice), by whole-body inhalation for 6 h/day, 5 days/week for up to 18 months. Postexposure blood samples were collected after 1 day, 2 weeks, and 3, 6, 12, and 18 months of exposure. Postexposure 16-h urine samples were collected after 2 weeks and 3, 6, 12, and 18 months of exposure. A separate set of mice was kept in the control chamber and exposed to 2BE for 3 weeks when they were approximately 19 months old. Postexposure blood samples were collected after 1 day and 3 weeks of exposure and 16-h urine samples were collected after 2 weeks of exposure from these aged mice. Blood samples were analyzed for both 2BE and 2BAA and urine samples were analyzed for 2BAA using GC/MS, and their kinetic parameters were estimated through the curve-fitting method using SAS. Systemically absorbed 2BE was rapidly cleared from blood (t1/2-RAT < 10 min; t1/2-MOUSE < 5 min after the 1-day exposure) independent of exposure concentration. Proportional increases in AUC2BE relative to increases in exposure concentration indicated linear 2BE kinetics. In contrast, the rate of 2BAA elimination from blood decreased as the exposure concentration increased. Nonproportional increases in AUC2BAA also indicated that 2BAA is eliminated following dose-dependent, nonlinear kinetics. Overall, mice eliminated both 2BE and 2BAA from blood faster than rats. Sex-related differences in 2BAA elimination were most significant with rats, in that females were less efficient in clearing 2BAA from the blood. Differences in renal excretion of 2BAA are possibly responsible for the sex-related difference in the 2BAA blood profiles in rats. As exposure continued, the rates of elimination for both 2BE and 2BAA decreased in both species, resulting in longer residence times in the blood. When 19-month-old naive mice were exposed to 125 ppm, 2BE was rapidly cleared from the systemic circulation, exhibiting clearance profiles similar to young mice. However, old mice eliminated 2BAA from blood > 10 times slower than young mice after 1-day of exposure. This delayed elimination of 2BAA in old mice was less obvious after 3 weeks of exposure, suggesting that there might be other factors in addition to the age of animals that could influence the apparent difference in 2BAA kinetics between old and young mice. It was concluded that the elimination kinetics of 2BE and 2BAA following repeated 2BE exposure appear to be dependent on species, sex, age, time of exposure, as well as the exposure concentration., (Copyright 1998 Academic Press.)

1. The elimination of 2-methoxyethanol (2-ME) and its toxic metabolite methoxyacetic acid (MAA) was studied in the male and female rat. We also studied the elimination of ethoxyacetic acid (EAA), the toxic metabolite formed by 2-ethoxyethanol (2-EE). 2. The rate of 2-ME elimination after i.p. injection of 2-ME (150 mg/kg) was significantly higher in the female compared with male. The elimination half-life was estimated to 49 +/- 10 min in the male and 28 +/- 5 min in the female. There was, however, no gender difference in the elimination of MAA after i.p. injection of 2-ME (100 mg/kg), and the elimination of MAA was markedly slower compared with 2-ME. The elimination half-life for MAA was estimated to 12.6 +/- 1.3 h in the male and 14.1 +/- 1.4 in the female. 3. The elimination half-life of EAA after i.p. injections of 100 mg/kg 2-EE was estimated to 7.6 +/- 1.1 h and 7.6 +/- 0.75 h in the male and female rat respectively. There was no gender difference in the elimination of EAA, but the rate of elimination of EAA was significantly higher compared with MAA. 4. Accumulation of the toxic metabolites MAA and EAA following frequent exposures to 2-ME and 2-EE respectively can then occur, and it remains to be determined whether there is a sex-difference in the susceptibility to toxic effects following exposure to 2-ME and 2-EE.

This study was carried out to provide information on the effects of inhalation of diethylene glycol monoethyl ether, a substance used in industry which may be accidentally inhaled by man. Sprague-Dawley CD rats were exposed by inhalation to a test atmosphere containing diethylene glycol monoethyl ether in a nose-only exposure system for 6 hr a day, 5 days a week for 28 days. Mean exposure levels were 0. 09, 0.27, and 1.1 mg/liter. At the two lowest exposure levels the test substance was present entirely as vapor, but at the highest exposure level the test atmosphere was approximately equally divided by mass into respirable droplets (aerosol) and vapor. A comprehensive battery of toxicological evaluations including food consumption, body weight, clinical signs, hematology, and biochemistry revealed no evidence of a systemic effect of exposure. Histopathological examination showed changes indicative of mild nonspecific irritation in the upper respiratory tract of rats exposed at the two highest exposure levels. These changes consisted of foci of necrosis in the ventral cartilage of the larynx of rats exposed at 0.27 or 1.1 mg/liter and an increase in eosinophilic inclusions in the olfactory epithelium of the nasal mucosa of rats exposed at 1.1 mg/liter. The no observed adverse effect level for systemic effects was 1.1 mg/liter and the no observed adverse effect level for signs indicative of mild nonspecific irritation of the upper respiratory tract was 0.09 mg/liter.

A high-performance liquid chromatography procedure for detection and quantitation of ethylene glycol in serum is described. Ethylene glycol and internal standard are derivatized with benzoyl chloride under alkaline conditions, purified by solid-phase extraction and analyzed by HPLC with UV detection. Analytical recovery of ethylene glycol ranges between 96 and 103%. The calibration curve is linear from 20 to 2000 mg/l. The limits of detection and quantitation are 10 and 20 mg/l, respectively. Assay imprecision is 4.8% or less. The assay is free from common interferences and provides increased sensitivity, improved precision and extended linearity.

The pharmacokinetics of [1,2-14C]ethylene glycol (EG) were evaluated in female Sprague-Dawley rats and CD-1 mice to characterize the plasma disposition after intravenous (IV), peroral (PO), and percutaneous (PC) doses. Rats were given doses of 10 or 1000 mg/kg by each route, and additional PO doses of 400, 600, or 800 mg/kg. Mice were also given IV and PO (bolus gavage) doses of 10 or 1000 mg/kg, and additional PO doses of 100, 200, or 400 mg/kg. PC doses in mice were 100 or 1000 mg/kg, and both species were given a 1000 mg/kg PC dose with a 50% (w/w) aqueous solution (2 ml/kg) to simulate antifreeze exposure. Results from this study have shown that orally-administered EG is very rapidly and almost completely absorbed in both rats and mice, with a bioavailable fraction of 92-100% in rats and similar percentages at the higher doses in mice. In contrast, the absorption of cutaneously applied EG is comparatively slow in both species. A species difference in the overall absorption of PC doses was demonstrated, with higher recoveries of 14C observed after PC doses in mice than for rats and a greater penetration of 14C after applying a 50% aqueous PC dose in mice than in rats, as evidenced by quantifiable plasma 14C concentrations only in mice. The major metabolites in both rats and mice are CO2 and glycolate. Oxidative metabolic pathways are saturated at high PO doses in both species, resulting in a shift from exhaled CO2 as the major excretion route to urinary excretion. The capacity to metabolize more completely EG to CO2 at low doses seems to be greater in the mouse than in the rat, as evidenced by the absence of urinary oxalate from EG-dosed female mice, and saturation of metabolic pathways at a comparatively lower dose in mice than for rats. This evidence suggests that dose-dependent changes in EG excretion in female Sprague-Dawley rats and CD-1 mice probably resulted from capacity-limited effects on EG metabolic pathways for the production of CO2 and a compensatory urine clearance of glycolate. Results from the present study corroborate previous observations in rats for the lower doses, but demonstrate a substantial difference in single-dose pharmacokinetics for IV and PO 1000 mg/kg doses in mice vs. rats. In summary, these data indicate that mice show a nonlinear plasma disposition of total radioactivity (EG and its metabolites) as dose is increased, whereas in rats plasma kinetics were linear over the dose range evaluated, whereas excretion kinetic patterns were nonlinear in both species as dose is increased.

1. The pharmacokinetic fate of [1,2-14C]-ethylene glycol (EG) was evaluated in the male Sprague-Dawley rat in order to characterize its overall uptake and elimination. Doses of 10 and 1000 mg/kg were administered by the intravenous (i.v.), peroral (p.o.), or percutaneous (p.c.) route; additional doses of 400, 600 and 800 mg/kg were evaluated by the p.o route. 2. Baseline data obtained by the i.v. route for bioavailability comparisons showed that while plasma radioactivity concentrations declined in a biexponential manner with t1/2 beta of 26-37 h, the disappearance of unmetabolized EG from the plasma was quite rapid (t1/2 beta of 0.8-1.2 h). Peroral doses were rapidly and almost completely absorbed, showing t1/2 abs in the order of minutes, and a bioavailable fraction for unmetabolized EG of 92-100%. Conversely, EG applied to rat skin was slowly and rather poorly absorbed, showing t1/2 abs which were an order of magnitude longer than for comparable p.o. and i.v. doses, and a bioavailability of approximately 22%. 3. The major route of elimination for the 10 mg/kg dose by any route was by metabolism to 14CO2 and exhalation, while urinary elimination of 14C was the secondary excretion pathway. 4. Plasma clearance of 14C was linear with increases in p.o. doses over the 400-800 mg/kg range, with AUC proportional to dose for these and the 10 mg/kg p.o. dose levels. However, a dose-dependent shift in excretion routes was observed following the p.o. 1000 mg/kg dose, with urine becoming the major excretion route, and similar capacity limited pharmacokinetics were observed for the i.v. 1000 mg/kg dose. Plasma pharmacokinetic data for unchanged EG after i.v. and p.o. doses demonstrated an apparent first-order kinetic behaviour between the 10 and 1000 mg/kg dose levels for the disappearance of EG. 5. Following both i.v. and p.o doses, dose-independent relationships were seen in the values obtained for the area under the plasma curve (AUC infinity), the total clearance of EG (CltotalEG), mean residence time (MRT infinity), apparent volume of distribution at steady state (Vdss), the terminal half-life (t1/2 beta) and the renal and metabolic clearance values. However, this dose-linear plasma time course was not apparent from the dose-dependent excretion profiles for these two exposure routes. 6. Increases in urinary 14C-glycolate were also observed when the i.v. or p.o. doses were increased from 10 to 1000 mg EG/kg, indicating that metabolism of EG makes a substantial contribution to AUC infinity in the beta disposition phase of the plasma curves for this high dose. Oxalate, a metabolite found in man after EG exposure, was detected at very low levels after both the 10 and 1000 mg/kg dose levels and by either i.v or p.o. routes. 7. Thus, EG given by three different routes demonstrated apparent first-order pharmacokinetic behaviour for disposition in and the elimination from plasma in the male rat, but dose-dependent changes occurred for the elimination of metabolites in urine and as 14CO2 after single i.v. and p.o. doses, but not for the p.c. routes.

Ingestion of methanol or ethylene glycol is a toxicologic emergency. The osmolal gap has been widely advocated as a screen for serum methanol or ethylene glycol. Unfortunately, for several reasons the osmolal gap fails in this capacity. First, an accurate serum osmolality can often not be obtained. Second, the calculated serum osmolarity will vary greatly, depending on the formula used to estimate it. Third, ethylene glycol has such a large molecular weight that even toxic amounts may contribute minimally to a patient's overall osmolality. Finally, because of metabolism, little ethylene glycol or methanol may be present when a patient presents with toxicity. These limitations invalidate the osmolal gap as a screen for ethylene glycol or methanol ingestion.

We developed a gas-chromatographic procedure for the simultaneous determination of ethylene glycol (EG) and its major toxic metabolite, glycolic acid (GA), suitable for clinical use in instances of EG intoxication. After serum protein precipitation with acetonitrile (containing internal standard), the supernate is treated with 2,2-dimethoxypropane (containing dimethylformamide) to remove water, and the volume is then reduced by evaporation to <100 microL of dimethylformamide (but not to dryness). After trimethylsilyl derivatization, the resulting derivatives are analyzed by capillary column gas chromatography. Only 100 microL of serum is required and the entire determination, including calibrators and controls, takes <2 h. The method gives a linear response to at least 10 g/L EG and 5 g/L GA and has a limit of detection <10 mg/L. Intraassay CV is < or = 2.8% for EG (100 and 1000 mg/L) and GA (100 and 500 mg/L); between-day CV is < or = 6.5%. The absolute recovery from serum was 91% for EG and 77-82% for GA (200 and 2000 mg/L each). Relative to calibrators prepared bovine serum albumin (70 g/L), the recovery was 99-104% for EG (100 - 5000 mg/L) and 95-105% for GA (50 - 2500 mg/L). No clinically important interference was detected for >60 exogenous or endogenous compounds and drugs.

An analysis of ethylene glycol acute intoxication treatment results was performed in a group of 36 patients hospitalized within a five year period. Mean serum and urine glycol concentrations in the analyzed population ranged from 0-851 mg/dl (mean = 130 mg/dl) and from 12.4 to 930.0 mg/dl (mean 333 mg/dl), respectively. At the time of admission to the clinic 15 of 36 patients were deeply unconscious and mean acid-base balance values were as follows: pH 6.99, pCO2 16.7 mmHg, pO2 140.1 mmHg, HCO3 6.36 mmol/l, BE -29.6 mmol/l. Because of respiratory failure 21/36 patients (58.3%) required controlled ventilation and 24/36 (66.7%) underwent dialysis. Sixteen patients (44.4%) developed acute renal failure. Mean hospitalization period was 16 days (1-53). Eighteen patients (50%) died. The direct death mechanism in 15 patients (83.3%) was asystolia and in the remaining individuals other circulatory disturbances. The main reasons of high mortality rate were multiple organ damages secondary to severe metabolic acidosis.

Case Reports: Two patients severely intoxicated with ethylene glycol became anuric and were treated by hemodialysis and the antidote, 4-methylpyrazole. On admission, their plasma ethylene glycol concentrations were 0.42 and 3 g/L respectively and no alcohol was detected. The elimination of 4-methylpyrazole in the dialysate represented 45% of the total body elimination. Clearances of 4-methylpyrazole by hemodialysis were 80 mL/min and 52 mL/min respectively., Results: In such cases, the authors propose infusion of a 4-methylpyrazole loading dose of 10-20 mg/kg before dialysis and intravenous infusion of 1-1.5 mg/kg/h during the 8-12 hours of hemodialysis to compensate the loss in dialysate.

Ethylene glycol poisoning is a common problem and identification of ethylene glycol in serum is important for both medical and legal purposes. Other glycols like propylene glycol, 2,3-butanediol, and diethylene glycols are also abused. Common derivatization techniques to form cyclic ester of ethylene glycol work only for 1,2-diols and cannot derivatize other glycols like diethylene glycol. The authors describe novel derivatization technique of ethylene glycol (Molecular weight 62) using 4-carbethoxyhexafluorobutyryl chloride that produces a distinct protonated molecular ion peak at m/z 563 in chemical ionization mode, thus aiding in unambiguous confirmation of ethylene glycol. The authors' novel derivatization technique is not limited to 1,2-diols and can derivatize any glycol. It yields less volatile derivatives than any conventional derivatives and is free from interference from the serum matrix. Moreover, those glycols produce distinctively different mass spectra compared to ethylene glycol. Quantitation of ethylene glycol can be easily achieved by using 1,2-butanediol as an internal standard. The assay showed a within run and between run precision of 6.7% and 8.2% and a linearity from 1.1-36.1 mmol/L (70-2,240 micrograms/mliters) of serum ethylene glycol concentration.

We describe a case of 2 siblings aged 2 1/2 and 3 1/2 yrs accidentally poisoned by ethylene glycol ingestion. We found estimating the level of ethylene glycol in plasma by calculation of osmolar gap too insensitive to be of value and advocate the availability of a specific method. In our study only one of the 2 children had a toxic level of ethylene glycol but assay by conventional assay and by proton magnetic resonance spectroscopy (1HMRS) of toxic metabolites viz glycolate, glyoxylate and oxalate showed both to be excreting grossly elevated levels. This indicates the desirability of assaying the toxic metabolites of the glycol as well as the parent compound in assessing ingestions.

Ethylene glycol poisoning is a common clinical problem and identification as well as quantitation of ethylene glycol in serum is important for medical and legal purposes. Most investigators described determination of ethylene glycol by gas chromatography without derivatization or derivatives forming a molecular ion < 200. We describe a novel derivatization technique of ethylene glycol using perfluorooctanoyl chloride, after extraction from serum using acetone. This derivative has a molecular mass of 854 and produces a base peak at m/z 441 and other diagnostic strong peaks for unambiguous identification. Moreover, this derivative is less volatile and is free from interferences from endogenous serum components. Quantitation can be achieved by using 1,4-butanediol as an internal standard. The assay showed within-run and between-run precision of 7.2% and 8.0%, respectively, and linearity over the serum ethylene glycol concentration range 70-2240 micrograms/ml with a detection limit of 5 micrograms/ml.

A sensitive and selective gas chromatographic-negative-ion chemical ionization mass spectrometric method was developed to simultaneously quantitate 2-butoxyethanol (BE) and butoxyacetic acid (BAA) in rat and human blood at low ng/g levels as pentafluorobenzoyl and pentafluorobenzyl derivatives, respectively. Analysis of 13C-labeled analogs of BE and BAA were found to improve the limits of quantitation to below 2 ng/g. Deuterium-labeled BE and BAA were used as internal standards. Calibration curves were generally linear over three orders of magnitude, with limits of quantitation of 16-18 ng/g for both BE and BAA, and 1.5 and 0.4 ng/g for [13C2]BE and [13C2]BAA, respectively, in human blood. Linearity in rat blood was similar, with limits of quantitation of 22 ng/g for BE and 5 ng/g for BAA. This method was developed for the support of mammalian metabolism studies and human biomonitoring studies involving exposure to BE or [13C2]BE.

We developed a packed-column chromatographic procedure capable of simultaneous quantitation of methanol, ethanol, isopropanol, acetone, and ethylene glycol. This method was then updated to a rapid, sensitive, wide-bore capillary method. The packed-column system uses direct injection of 1 microL of Na2WO4/H2SO4-deproteinized serum onto a 1.8 m x 2 mm (i.d.) column packed with 80/100 HayeSep R. A linear temperature gradient from 90 to 205 degrees C allows complete elution of all components within 20 min; minimum detection limits are 2 mmol/L. The wide-bore capillary method uses 0.1 microL of sample deproteinized by ultrafiltration, injected onto a 30 m x 0.53 mm (i.d.) 3-microns Rtx-200 (Restek) column. Baseline resolution to a minimum detection limit of 0.1 mmol/L of all compounds is achieved in 5 min with a linear temperature gradient from 40 to 250 degrees C and dual internal standards of n-propanol and 1,2-butanediol.

A physiologically based pharmacokinetic model was developed to describe the disposition of 2-butoxyethanol (CAS 111-76-2) and its major metabolite, 2-butoxyacetic acid, in rats and humans. A previous human inhalation model by Johanson (Toxicol. Lett. 34, 23 (1986)) was expanded to include additional routes of exposure, physiological descriptions for rats, competing pathways for metabolism of 2-butoxyethanol, and measured partition coefficients for 2-butoxyethanol and 2-butoxyacetic acid. Simulations were compared to data gathered from rats following either intravenous infusion or oral or inhalation exposure and from humans following either inhalation or dermal exposure to 2-butoxyethanol. It was necessary to add equations for both protein binding of 2-butoxyacetic acid in blood and saturable elimination of 2-butoxyacetic acid by the kidneys to consistently describe the data. While the model predicted that rats metabolize 2-butoxyethanol and eliminate the acid metabolite faster per kilogram body weight than humans, the balance of these two processes in addition to physiological differences between species resulted in higher predicted peak blood concentrations as well as total areas under the blood concentration time curves for 2-butoxyacetic acid for rats versus humans. These species differences in kinetics coupled with the fact that human blood is significantly less susceptible than rat blood to the hemolytic effects of 2-butoxyacetic acid indicate that there is considerably less risk for hemolysis in humans as a result of exposure to 2-butoxyethanol than would have been predicted solely from standard toxicity studies with rats.

We present three patients with ethylene glycol antifreeze poisoning whose management included the use of continuous veno-venous haemodiafiltration. Results from these cases demonstrate clearance of the ethylene glycol molecule.

An automated kinetic method for assaying ethylene glycol in serum using glycerol dehydrogenase with the multiparametric analyzer Cobas Mira is described. Initially, 5 microL of sample is mixed with tris-NAD buffer; after enzyme addition, the variation of the absorbance at 340 nm is automatically measured, and the instrument calculates the ethylene glycol concentration of the specimen. The method has good precision and specificity and is suitable for emergency screening. Some applications developed in our laboratory are also described.

A survey was conducted to check the toxicological impact of ethylene glycol present in a thermal decomposition mixture of type C hydraulic fluid on laboratory animals submitted to an inhalation test. The target organs, i.e. kidneys, of exposed rats were evaluated histologically and oxalic acid--the ethylene glycol metabolite thought to cause renal failure--was quantified in urine samples. The results show that the low ethylene glycol concentrations present in the inhalation chamber produce only a temporarily increased oxalic acid excretion, at levels that are not significant. These findings are supported by the histological evaluation of the kidneys showing no calcium oxalate deposits or other abnormalities.

Coma with grave metabolic acidosis, increased anion and osmolal gap, oxalate crystals in urine sediment and increased ultrasound density of the renal parenchyma are essential clues to the diagnosis of ethylene glycol poisoning. Envelope-like dihydrate calcium oxalate crystals are usually found in the sediment of these patients. We describe a patient with needle and cigar-shaped monohydrate calcium oxalate crystals in urinary sediment, but no detectable ethylene glycol in blood tests taken upon arrival at hospital 12 hours after ingestion. The patient was treated with alkali and haemodialysis, and recovered without any sequelae. Monohydrate calcium oxalate crystals were an essential clue for diagnosis of ethylene glycol poisoning in this patient.

1. Osmolal and anion gaps are helpful in the diagnosis and evaluation of intoxications with methanol and ethylene glycol. Reported reference values for osmolal gap and anion gap are -1 (+/- 6) mosm kg-1 H2O and 16 (+/- 2) mmol l-1, respectively. However, we have repeatedly found unexplained increased gaps in patients admitted to our department, and the relevance of the established reference values has been questioned. 2. Osmolal and anion gaps were determined in an unselected population of patients consecutively admitted to an emergency medical department. In the case of unexplained gaps, the blood samples were analysed with respect to the presence of alcohols and organic acids. 3. We included all accessible patients admitted during 14 days. Appropriate blood samples were obtained in 177 patients (88 male, 89 female), with a mean age of 65 years (range 17-94). 4. The mean and (standard deviation) for osmolal and anion gaps in our material were 5.2 mosm kg-1 H2O (7.0) and 12.9 mmol/l (4.2). Neither methanol nor ethylene-glycol was detected in serum from any patients. Small amounts of ethanol were found in 5 patients, and high lactate levels explained in part the most extensively increased anion gaps. However, the calculated analytical standard deviation accounted entirely for the variation in our material, and we suggest that the present reference values be adjusted.

Potentially fatal ethylene glycol intoxication in an adult with normal renal function was treated with 4-methylpyrazole administered three hours after the incident occurred. The plasma ethylene glycol concentration was 3.5 g l-1 on admission. The metabolic acidosis present on admission resolved within four hours, and the subsequent clinical course was uneventful. The apparent plasma half-life of ethylene glycol was 16 h and the mean renal and plasma clearances of ethylene glycol were 24 and 25 ml min-1, respectively. These results support the hypothesis that complete blockade of hepatic metabolism of ethylene glycol is achieved by 4-methylpyrazole. The only side-effect observed as a result of treatment was a transient slight increase in serum transaminase activity.