ATTEMPTED UXORICIDE

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INTRODUCTION

In early 2006 a man tried to poison his wife using paraflú which mainly consist of Ethylene glycol , mixing that with a liquid drugs mix the woman was assuming at that period to undergo a colonoscopy. The woman was suddenly carried at the emergency room of the nearer hospital in a condition of unexplained coma.
When ER's physicians realized that the problem was an abnormal form of poisoning, they decided to ask for an opinion to doctors from hygien department in Turin that in a few hours found out the antidote to save her.

BIOCHEMISTRY

Synonyms	1,2-Ethanediol, ethylene alcohol, 1,2-dihydroxyethane,ethylene dihydrate, glycol
CAS number	107-21-1
IMIS	1911
RTECS	KW2975000
Molecular weight	62,08
Boiling point	197,5° C
Melting point	-13 ° C
Flash point	232 ° F
Vapor pressure	0,05mm @ 20°C
Density	1,113 @25°C/25°C
Properties	hygroscopic liquid
Solubility	Miscible with water and alcohol; slightly soluble in ether; insoluble in benzene and its homologs, chlorinated hydrocarbons, and petroleum ethers
Molecular formula	C2H6O2

It is the simpler bivalent alcohol.
EG (IUPAC name: ethane-1,2-diol) is an organic compound primarily used as a raw material in the manufacture of polyester fibers and fabric industry, and polyethylene terephthalate resins (PET) used in bottling. A small percent is also used in industrial applications like antifreeze formulations and other industrial products. It is an odorless, colorless, syrupy, sweet-tasting liquid. Ethylene glycol is only weakly toxic, but cases of poisonings are not uncommon.
Ethylene glycol is produced from ethylene (ethene), via the intermediate ethylene oxide. Ethylene oxide reacts with water to produce ethylene glycol according to the chemical equation:
C2H4O + H2O → HO–CH2CH2–OH

This reaction can be catalyzed by either acids or bases, or can occur at neutral pH under elevated temperatures. The highest yields of ethylene glycol occur at acidic or neutral pH with a large excess of water. Under these conditions, ethylene glycol yields of 90% can be achieved. The major byproducts are the ethylene glycol oligomers diethylene glycol, triethylene glycol, and tetraethylene glycol.
Ethylene glycol disrupts hydrogen bonding when dissolved in water. Pure ethylene glycol freezes at about −12 °C (10.4 °F), but when mixed with water, the mixture does not readily crystallize, and therefore the freezing point of the mixture is depressed. Specifically, a mixture of 60% ethylene glycol and 40% water freezes at −45 °C (−49 °F). Diethylene glycol behaves similarly. It is used as a de-icing fluid for windshields and aircraft. The antifreeze capabilities of ethylene glycol have made it a component of vitrification (anticrystallization) mixtures for low-temperature preservation of biological tissues and organs.
However, the boiling point for aqueous ethylene glycol increases monotonically with increasing ethylene glycol percentage. Thus, the use of ethylene glycol not only depresses the freezing point, but also elevates the boiling point such that the operating range for the heat transfer fluid is broadened on both ends of the temperature scale. The increase in boiling temperature is due to pure ethylene glycol having a much higher boiling point and lower vapor pressure than pure water; there is no chemical stabilization against boiling of the liquid phase at intermediate compositions, as there is against freezing.
Ethylene glycol is poorly toxic for mammals in general, but it is moderately toxic for humans, we can have death' s risks even with 398 mg/*kg*.
The major danger is due to its sweet taste, because of that children and animals are more inclined to consume large quantities of it than of other poisons. Upon ingestion, ethylene glycol is oxidized to glycolic acid which is, in turn, oxidized to oxalic acid, which is toxic.
These metabolites cause metabolic acidosis with increased anion gap, renal failure, oxaluria, damage to the central nervous system and cranial nerves, and cardiovascular instability. Early initiation of treatment can reduce the mortality and morbidity but different clinical presentations can cause delayed diagnosis and poor prognosis.
According to the annual report of the American Association of Poison Control Centers' National Poison Data System in 2007, there were about 1000 total cases resulting in 16 deaths, in 2008 just 7.

BODY'S DAMAGES

As we wrote at beginning this woman has ingested a moderate amount of EG, which brought her to hospital in coma that could be explained both with kidney failure and direct EG's effects on central nervous system.
Lower doses are toxic to humans even by subcutaneous, intravenous, and intramuscular routes.

Human Systemic effects by ingestion and inhalation: eye lacrimation, general anesthesia, headache, cough, respiratory stimulation, nausea or vomiting, pulmonary, kidney and liver changes. After the ingestion it causes initial central nervous system stimulation followed by depression, later it causes potentially lethal kidney damage. Ethylene glycol has shown to be teratogen. It is a skin, eye, and mucous membrane irritant.

According to the US dipartement of labour the lethal dose for humans is reported to be 100 mL.

Symptoms of ethylene glycol poisoning usually follow a three-steps porgression, although not every case do.
Stage 1 (0,5 to 12 hours) consist of neurological and gastrointestinal symptoms; people may appear to be intoxicated, exhibiting symptoms such as dizziness, incoordination of muscles movements, nystagmus, headaches, slurred speech and confusion. Irritation to the stomach may cause nausea and vomiting. Over time, the body metabolized ethylene glycol into other toxins.

Stage 2 (12 to 36 hours) is a result of accumulation of organic acids formed by the metabolism of ethylene glycol and consists of increased heart rate, hight blood pressure, hyperventilation and metabolic acidosis. Additionally low calcium concentration in the blood, overactive muscle reflexes, muscle spams, QT interval prolongation and congestive heart failure may occur. If untreated death most commonly occurs during this period.

Stage 3 (24 to 72 hours) kidney failure is the result of ethylene glycol poisoning. Symptoms include acute tubular necrosis, red blood cells in the urine, excess proteins in the urine, lower back pain, decreased or absent production of urine, elevated blood concentration of potassium and acute kidney failure, which is normally reversible.

After the ingestion EG is metabolised via alcohol dehydrogenase to glycolaldehyde which is rapidly metabolised to glycolate, the metabolite mainly responsible for the metabolic acidosis in ethylene glycol poisoning.
Glycolate is metabolised by various pathways, including one to oxalate which rapidly precipitates with calcium in various tissues and in the urine. Ethylene glycol toxicity is complex and not fully understood, but is mainly due to the severe metabolic acidosis caused by glycolate and to the calcium oxalate precipitation. The first reaction we assist to is metabolic acidosis then victims develop renal and cardiopulmonary failure. The increase of metabolites may be the cause of encephalopathy and cerebral edema.
Additionally, as a side effect of the first two steps of metabolism, an increase in the blood concentration of lactic acid occurs contributing to lactic acidosis. The formation of acid metabolites also causes inhibition of other metabolic pathways, such as oxidative phosphorylation.
The renal toxicity of ethylene glycol is caused by a direct cytotoxic effect of glycolic acid. The glycolic acid is then metabolized to glyoxylic acid and finally to oxalic acid. Oxalic acid binds with calcium to form calcium oxalate crystals which may deposit and cause damage to many areas of the body including the brain, heart, kidneys, and lungs. The most significant effect is accumulation of calcium oxalate crystals in the kidneys which causes kidney damage leading to oliguric or anuric acute kidney failure.
("In case of renal failure": http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835194/#!po=90.0000) we can observe that kidneys present widespread necrosis of the tubular epithelium and deposition of a multitude of doubly refractile oxalate crystals in the distal tubules and collecting ducts.
The renal failure is considered to be the last stage of this kind of poisoning (it can occur even after 48 h), though the situation has been described full recovery can be observe.

The rate-limiting step in this cascade is the conversion of glycolic to glyoxylic acid. Accumulation of glycolic acid in the body is mainly responsible for toxicity.

Prognosis is excellent provided that there is early treatment with alkali to combat acidosis, ethanol as an antimetabolite, and haemodialysis to remove the alcohols and their toxic metabolites. Ethanol is metabolised too by alcohol dehydrogenase and because of his higher affinity for that is able to reduce the creation of toxic metabolites.

To sum up:

• metabolic acidosis (increased anion gap, difference between measured cations and anions);
• renal failure;

• Oxaluria;
• damage to the central nervous system and cranial nerves;
• cardiovascular instability.

LABORATORY ANALYSIS

In the context of laboratory medicine there are chances of identifying substances in the body that in abnormal concentrations testify their absorption. When the woman was carried to the hospital saples of blood, urine, serum and gastric juice were analyzed.
The primary method for measuring ethylene glycol in biological samples is derivatization followed by gas chromatography (*GC*) using either a flame ionization detector (*FID*) or mass spectrometry (*MS*) for quantification. GC is the preferred analytical method because of the ease of sample preparation and the accuracy of the quantification of sample concentrations: to perform the dose of GC, the samples (urine, blood or gastric juice) are diluted with methanol, treated in a 1:1 ratio. In cases of acute poisoning, where it is useful to further confirmation, the sample is analyzed with GC-MS.
Sample preparation for GC is important and proceeds through several steps: acidification, esterification and extraction into an organic solvent. The use of internal standards is necessary for quantification. Detection of ethylene glycol in biological samples using GC with either FID or MS is very sensitive, with detection limits ranging from sub to low ppm. The coefficient of variation (CV) varies with the concentration of glycol used but typically ranges from 0.4 to 27% and is usually <10%. In GC procedures, the glycols and their acid metabolites are derivatized to form esters in order to facilitate quantitative elution from the chromatographic columns. Yao and Porter (1996) and Porter et al. (1999) have developed a procedure for the simultaneous determination of ethylene glycol and glycolic acid in human serum. The entire procedure can be completed in <2 hours. Simple and rapid methods are also available for the quantitation of the glycols in urine, serum, or deproteinated whole blood. These methods use direct sample injection without prior solvent extraction and derivatization. (In this regard see "table": http://www.atsdr.cdc.gov/toxprofiles/tp96-c7.pdf)

High performance liquid chromatography (*HPLC*) has also been used to identify ethylene glycol and its metabolites such as glycolate hippurate and oxalate in biological samples, particularly blood and urine. Positive results may be confirmed with GC/MS. This makes GC/MS the preferred method since the HPLC step can be omitted. However, HPLC methods to measure plasma levels of glycolate have been used to aid in diagnosis and treatment of ethylene glycol poisoning.
Techniques using GC and various detection systems to detect and quantify ethylene glycol in human blood have been developed for use in hospital laboratories to assist in the diagnosis of ethylene glycol poisoning (caused by drinking antifreeze containing ethylene glycol). These techniques are quite rapid, usually <30 minutes, and do not require elaborate sample preparation. _Microscopy_ can be used to identify metabolic products of ethylene glycol. Scanning electron microscopy (SEM) at 20 kilovolts will detect crystals of calcite, calcium oxalate monohydrate, and calcium oxalate dihydrate in kidney tissue. Phase-contrast polarization and light microscopy X-ray powder diffraction may be used to identify hippuric acid crystals in urine. An alternative method, developed in a hospital, for detecting ethylene glycol in blood is the use of the _DuPont Automated Clinical Analyzer triglyceride assay pack_. This enzymatic method, while relatively simple, cannot be used when the triglyceride concentration of the serum exceeds 12 g/L and requires that positive results for ethylene glycol be confirmed using another method. The enzymatic method has been modified to eliminate some of the interference problems present in the earlier methods. _Thin-layer chromatography_ (*TLC*) with a chloroform solvent has been used to detect ethylene glycol and its metabolites in urine or renal tissue. Metabolites of ethylene glycol in the blood may be detected by analytical isotachophoresis using a system equipped with both a conductivity detector and an ultraviolet detector. Blood and serum samples should not have been previously treated with oxalate, citrate, or ethylene diamine tetracetic acid. This technique may be of value when ethylene glycol poisoning is suspected but sufficient time has elapsed for metabolism of the compound to have occurred. A simple and rapid colorimetric method that uses chromatropic acid has been proposed for the quantitation of glycolic acid, the major toxic metabolite of ethylene glycol. No information was located on detecting ethylene glycol in feces, adipose tissue, or human milk As with biological samples, GC is the major technique used to determine ethylene glycol concentrations in environmental samples whether in *air*, *water*, *food*, *drugs*, or other substances. _Capillary gas chromatography_ with FID or ECD, possibly followed by MS, generally gives good quantitative results down to the ppm range with recovery usually >80%. The determination of ethylene glycol in air requires adsorption onto a surface and subsequent extraction. Water samples may be analyzed without preparation. Detection of ethylene glycol in foods and drugs may be accomplished by chromatography of the sample; for substances with a high fat content, extraction with hexane may be used to remove the fat.
Air sampling for ethylene glycol is performed by adsorption onto a resin column such as Amberlite XAD-2. Although activated charcoal filters have some utility, recovery is greater with the Amberlite, and it is the preferred adsorption medium. Ethylene glycol is then solvent-extracted with recovery of 98%. If activated charcoal is used for adsorption, 5% methanol in dichloromethane is the best solvent with maximum recovery of 84%. An alternative method for sampling ethylene glycol involves passage of air through a glass fiber filter with a silica gel tube. Ethylene glycol is then extracted in a 2-propanol:water solvent mixture and injected into the gas chromatograph . A similar version of this method is the NIOSH-approved method for the determination of ethylene glycol in occupational air. A portable, automated, photoionization gas chromatograph has been used to detect ethylene glycol in air samples in industrial facilities at levels as low as 0.05 ppm.
Ethylene glycol may be detected by a colorimetric reaction with 3-methyl-2-benzothiazolinone hydrazone hydrochloride after oxidation of the glycols to the corresponding aldehydes with acidified permanganate. The solution is read at 630 nm in a spectrophotometer. This method may be used for ethylene glycol in water or to detect ethylene oxide in air; however, this method is not quantitative and is relatively insensitive compared with GC/MS.
The migration of ethylene glycol from plastics into solutio can be studied with GC. Sample preparation methods include extraction in hydrochloric acid, distilled water, carbon disulfide, dimethylformamide, and a mixture of ethyl acetate, water and methanol. Other methods for detecting ethylene glycol in industrial products include HPLC and a periodate follow-through ion-selective electrode.
The presence of ethylene glycol in foods packaged with plastic films containing the compounds has been studied, as have ethylene glycol levels in drugs sterilized with ethylene oxide. Sample preparation is important because procedures vary depending on the fat content of the food sample. Foods with low fat content can be extracted with ethyl acetate, derivatized to a trimethylsilyl ether, and then injected into the gas chromatograph. For foods with a high fat content, hexane is used as the defatting agent prior to derivatization. Quantifying ethylene glycol in wines requires no preparation of the samples prior to analysis. Drugs in aqueous solutions may be analyzed directly, water insoluble drugs should be extracted in water, and ointments may be dissolved in hexane and then extracted with water. Recovery is between 80 and 114%, with detection limits in the low-ppm range. Although the use of TLC has been recommended, it has been superseded by GC.
No information was located on techniques for detecting and analyzing ethylene glycol in soil.
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