Technical Note: Glycolic Acid Exacerbates the Analytical Performance of Lactate Assay.

In this study, we evaluated the analytical interference of glycolic acid on several lactate assays that use lactate oxidase and dehydrogenase. Herein, we tested the effect of different concentrations of glycolic acid (0.01-46mM) on the lactate assay by using central lab and point of care (POCT) analyzers: Radiometer ABL 800, Beckman AU480, Roche Cobas c502, and Abbott i-STAT. Glycolic acid concentrations as low as 0.12mM resulted in a ≥20% positive bias in lactate assay on the ABL 800 and a concentration of approximately 0.23mM resulted in >20% on the Roche Cobas c502 and Abbott i-STAT. A significant lactate gap is found at concentrations >0.06mM between the Radiometer ABL 800 and Roche Cobas c502/Abbott i-STAT. However, at concentrations ≥0.92mM, the lactate gap is very significant among all three platforms. Falsely elevated lactate levels could result in misdiagnosis.

A case of fatal intoxication by ingestion of an herbicide formulation containing fluroxypyr-meptyl and triclopyr.

Fluroxypyr-meptyl and triclopyr are synthetic auxin-like herbicides that are used to control woody and broadleaf weeds. Herein, we report a case of fatal intoxication involving fluroxypyr-meptyl and triclopyr. A 61-year-old man was found dead at his farm with several suicide notes, and a white plastic bottle and a plastic cup with traces of white emulsion were found next to him. The plastic bottle was labeled as an herbicide formulation containing fluroxypyr-meptyl and triclopyr. Forensic toxicological screening of the stomach contents revealed the presence of fluroxypyr-meptyl, fluroxypyr and triclopyr. However, no fluroxypyr-meptyl was detected in blood owing to its rapid hydrolysis to fluroxypyr. In this study, fluroxypyr and triclopyr in blood were extracted using solid-phase extraction, and analyzed by liquid chromatography-tandem mass spectrometry. The analytical method was validated in terms of linearity, precision, accuracy, recovery and matrix effect, and the acceptable criteria were satisfied. Toxicological analysis showed that fluroxypyr and triclopyr concentrations were 19.7 µg/mL and 137.4 µg/mL in peripheral blood and 16.5 µg/mL and 147.8 µg/mL in heart blood, respectively. Based on these toxicological results and autopsy findings, the cause of death was determined to be acute fatal intoxication by ingestion of the pesticide containing fluroxypyr-meptyl and triclopyr. This is the first report of the determination of fluroxypyr and triclopyr in a fatal intoxication case.

Life-threatening triclopyr poisoning due to diethylene glycol monoethyl ether solvent.

INTRODUCTION: Triclopyr is a synthetic auxin-like herbicide. It is considered to have low toxicity and there are few reports of poisoning. We report two cases of life-threatening toxicity following ingestions of 250 mL of 50 g/L triclopyr co-formulated with diethylene glycol monoethyl ether (DEGEE). CASE REPORTS: A 79-year-old male with a background of hypertension and atrial fibrillation presented two hours after ingestion with sedation, a severe high anion gap metabolic acidosis, raised osmolar gap and an aspiration pneumonitis. He was ventilated and dialysed for 10 h with resolution of the acidaemia. He was discharged home on day 33. A 66-year-old male with a past history of alcoholism and hypertension presented following a collapse. He had sedation, a severe high anion gap metabolic acidosis with a raised osmolar gap, acute kidney injury and vasodilatory shock. He was ventilated and received dialysis for 43 h. He had poor neurological recovery and died on day 10. DISCUSSION: Ingestion of triclopyr formulations can produce life-threatening toxicity. In large poisonings of triclopyr co-formulated with DEGEE, a high anion gap metabolic acidosis appears to be due to the glycol ether solvent rather than triclopyr itself. Management should focus on good supportive care including dialysis for significant metabolic acidosis.

Fast determination of ethylene glycol, 1,2-propylene glycol and glycolic acid in blood serum and urine for emergency and clinical toxicology by GC-FID.

A simple, cost effective, and fast gas chromatography method with flame ionization detection (GC-FID) for simultaneous measurement of ethylene glycol, 1,2-propylene glycol and glycolic acid was developed and validated for clinical toxicology purposes. This new method employs a relatively less used class of derivatization agents - alkyl chloroformates, allowing the efficient and rapid derivatization of carboxylic acids within seconds while glycols are simultaneously derivatized by phenylboronic acid. The entire sample preparation procedure is completed within 10 min. To avoid possible interference from naturally occurring endogenous acids and quantitation errors 3-(4-chlorophenyl) propionic acid was chosen as an internal standard. The significant parameters of the derivatization have been found using chemometric procedures and these parameters were optimized using the face-centered central composite design. The calibration dependence of the method was proved to be quadratic in the range of 50-5000 mg mL(-1), with adequate accuracy (92.4-108.7%) and precision (9.4%). The method was successfully applied to quantify the selected compounds in serum of patients from emergency units.

Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning.

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.

The 'gap' in the 'plasma osmolar gap'.

Ethylene glycol poisoning is a medical emergency that presents challenges for clinicians and clinical laboratories. If left untreated, it may cause morbidity and death, but effective therapy is available if diagnosed in time. The diagnosis of ethylene glycol poisoning is not always straightforward and the commonly quoted 'plasma osmolar gap' is not sufficiently sensitive to exclude a small ingestion and has been reported to be normal in a number of serious exposures. The 'plasma osmolar gap' cannot distinguish among ethanol, isopropyl alcohol, methanol or ethylene glycol. Thus, the measurement of serum ethylene glycol and, ideally, glycolic acid, its major toxic metabolite in serum, is definitive. This also holds true for methanol and its metabolite formic acid. Ethylene glycol metabolites target the kidney and lead to reversible oliguric or anuric injury, which in turn slows the elimination of ethylene glycol. The therapeutic options include reversal of metabolic acidosis, inhibition of alcohol dehydrogenase and early haemodialysis.

Clinical outcome of acute intoxication due to ingestion of auxin-like herbicides.

BACKGROUND: The human toxicity of synthetic auxin analogue herbicides has not been extensively studied. METHODS: Clinical outcome was assessed from medical records of 17 patients who had intentionally ingested auxin pesticides with active ingredients like dicamba, triclopyr, MCPA or mecoprop. The patients were interviewed after discharge to follow outcome (interval 2 to 56 months). RESULT: One patient who had ingested 500 mL of a mecoprop product died of hypotension and respiratory failure 36 hours after hospital admission. The other 16 patients recovered and were discharged by hospital day 28. After discharge, four patients died from causes not related to herbicide intoxication. In the 12 surviving patients, no long-term effects were reported. CONCLUSION: Human toxicity of synthetic auxins appears relatively benign with conservative treatment. However, when the amount ingested is above several hundred milliliters of commercial product, especially in combination of mecoprop with other intoxicants (e.g. alcohol), shock with respiratory failure may develop and lead to death.

Severe systemic intoxication following triclopyr-TEA ingestion.

We report a case of triclopyr ingestion, a herbicide that acts via the auxin system in plants. It is classified as low-toxicity herbicide. The patient ingested this product and developed metabolic acidosis and coma with cardiovascular impairment. Echocardiography and elevated Troponin T and CK MB with prolongation of QTc suggested direct myocardial toxicity. The patient was extubated 57 h after ingestion, and he recovered completely. This case illustrates the potential acute toxicity of this agent in humans.

Clinical toxicologic implications of ethylene glycol and glycolic acid poisoning.

Metabolic pathways have been elucidated for various chemical and solvent exposures in humans. Clinical laboratory analyses in most chemical and solvent exposures are directed toward identification and quantitation of unchanged substance in serum or whole blood. For example, most laboratories routinely screen for unchanged ethylene glycol in suspected poisonings and quantitate ethylene glycol in positive cases even though toxicity from ethylene glycol exposure (including central nervous system depression, acute renal failure, and elevated anion gap metabolic acidosis) is primarily caused by one metabolite-glycolic acid. One objective of this manuscript is to describe the authors' clinical experience with glycolic acid analysis in ethylene glycol human poisonings. Recommended clinical laboratory tests for small hospitals and toxicology reference laboratories are presented to rule out or confirm ethylene glycol exposure. Another concern with laboratory support in ethylene glycol poisoning is correct identification of ethylene glycol because analysis of this substance is often problematic. In one case laboratories incorrectly identified an organic acid from an inherited metabolic disease as ethylene glycol, and in another case the intentional ethylene glycol poisoning of an infant was determined to be the results of an endogenous organic acid. The most robust analytical methods for determining ethylene glycol and glycolic acid are chromatographic methods. Ideally, screening methods for ethylene glycol should be confirmed by another method based on a different principle of analysis or include simultaneous metabolite analysis (glycolic acid). In centers where several ethylene glycol cases present annually, toxicology laboratories supporting these centers should incorporate glycolic acid monitoring in their ethylene glycol screening programs and include analysis of both ethylene glycol and glycolic acid during treatment (hemodialysis) in all confirmed poisonings. Measurement of glycolic acid provides important diagnostic and prognostic information that one cannot correlate with the amount of ethylene glycol in serum or whole blood.

Rapid determination of ethylene glycol and glycolic acid in biological fluids.

Ethylene glycol poisoning of companion animals is a common occurrence and is sometimes involved in human intoxication. Ethylene glycol is of limited toxicity, but the metabolites including glycolic acid are responsible for poisoning. Conventional treatment has employed substances to prevent alcohol dehydrogenase from metabolizing the ethylene glycol, but to be effective, therapy must begin within hours of ethylene glycol consumption. We describe a rapid (10 min) analysis of biological fluids for ethylene glycol and glycolic acid using isocratic HPLC, a refractive index detector, and a Waters fast fruit juice analytical column.

Association between soft tissue sarcomas, malignant lymphomas, and phenoxy herbicides/chlorophenols: evidence from occupational cohort studies.

Some case-control studies have reported a significant association between occupational use of phenoxy herbicides and chlorophenols and soft-tissue sarcomas and malignant lymphomas. However, persons who spray or apply these substances are concomitantly exposed to other potentially carcinogenic chemicals and oncogenic viruses, which have been found or suspected to play a role in the etiology of these tumors. No study has thoroughly controlled for these other exposures, some of which have been shown to be independently associated with these tumors even after controlling for exposure to phenoxy acids or chlorophenols. On the other hand, it has been found that an observed risk from exposure to phenoxy herbicides disappeared on controlling for some of these concomitant exposures in the rare instance this was attempted. Also, on several occasions, an association has been observed with occupations in which exposure to phenoxys and chlorophenols may occur, but not with the compounds themselves. Accordingly, a detailed review of the evidence from occupational cohort studies was conducted, to see if it corroborates that from case-control studies. It was found that the evidence does not unequivocally incriminate phenoxys and chlorophenols as a cause of these tumors. The results obtained with cohort studies of sprayers and applicators do not corroborate the association reported among this occupational group, in case-control studies. It is possible that the suspected association may well be due, partly or wholly, to one or more of the other concomitant exposures. However, in view of the fact that the majority of the cohorts need further follow-up to be informative, it is concluded that further studies of these cohorts are required before it can be determined whether or not these tumors are caused by exposure to phenoxy acids and chlorophenols.

Delayed sudden death after ingestion of MCPP and ioxynil: an unusual presentation of hormonal weedkiller intoxication.

A patient who died in asystole less than 18 h after ingestion of 'Clovercide Extra', a combination hormonal weedkiller containing ioxynil and 4-chloro-2-methyl phenoxypropionic acid, is described. Previous reports describe coma as an early event following ingestion of these herbicides. In contrast our patient, although showing other characteristic features, including metabolic acidosis, tachycardia, pupillary constriction and pyrexia, remained conscious until the terminal event. Absence of coma does not appear to be related to a more favourable outcome.

Acute MCPP intoxication: report of two cases.

1. Two cases of serious intoxication with phenoxy herbicides (MCPP) are reported. 2. Both patients had central nervous system involvement, became unconscious and had an inadequate respiration. Muscle cramps and rhabdomyolysis with renal failure were noted in both. Shortly after admission both patients developed a serious decrease in arterial blood pressure (160/80 mmHg to 80/45 mmHg). In one patient this was demonstrated to be caused by a reduction in peripheral vascular resistance. 3. Plasma concentration of MCPP in patient 2 was 298 mg/l (3-4 h after ingestion). The plasma t1/2 was about 17 h. MCPP plasma elimination probably follows first-order kinetics.

Marked hypocalcemia in a fatal poisoning with chlorinated phenoxy acid derivatives.

A fatal poisoning with a herbicide which contains chlorinated phenoxy acid derivatives is reported with a special attention to the profound disturbances in calcium homeostasis related to an acute renal failure with hyperphosphatemia.

Phenoxy and picolinic acid herbicides and small-intestinal adenocarcinoma in sheep.

A study of age and sex matched groups of adult female sheep from 88 flat, hill, and high-country farms was conducted in the South Island of New Zealand to investigate the influence of breed and certain environmental factors on the prevalence rate of small-intestinal adenocarcinoma (SIA). 20 678 female sheep aged 5.5-7.5 years were examined at slaughter, 125 cases of SIA were found (6 per thousand) in animals from 61 farms (69%) and the prevalence rate for individual farm groups varied from 0 to 38 per thousand. Differences in tumour rate between breed groups were significant but differences between farm type were not. Exposure to phenoxy (Ph), picolinic acid (Pi) herbicides, or both (PhPi) was associated with significant increases in tumour rate. The increase in rate was significant for exposure to each of the 3 herbicide groups. Exposure to recently sprayed feed stuffs was associated with a significantly larger increase in tumour rate than exposure to less recently sprayed food. There was no difference between tumour rates of sheep exposed to Ph herbicides with or without 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rates rose significantly with the total number of Ph, Pi, PhPi sprays used on the farm. The variation in rates associated with herbicides is sufficient to explain the breed differences recorded.

Prolonged coma and delayed peripheral neuropathy after ingestion of phenoxyacetic acid weedkillers.

A case of prolonged coma and delayed peripheral neuropathy is reported following self-poisoning with a widely available domestic weedkiller containing phenoxyacetic acids. Attention is drawn to the potential toxicity of these weedkillers which may be delayed in onset, and to the possibility of spontaneous recovery from neurological abnormalities which may be severe and prolonged or late in onset.

[Electromyographic characteristics of acute poisonings with chlorine derivatives of phenoxy acids]. / Elektromiograficheskaia kharakteristika ostrykh otravlenii khlorproizvodnymi fenoksikislot.

In acute poisonings with chlorine derivatives of phenoxy acids, the myotonic period of poisoning is marked electromyographically by the manifestations specific and non-specific for myotonia. The characteristic signs involve multiple electrical responses of muscle fibers stimulated by a single excitation impulse--potential or myotonic discharges. Non-specific alterations are characterized by prolongation of the latent period, decreased amplitude and shortening of the length of evoked action potentials, which indicates the suppression of muscle excitability. Electromyographic changes are a consequence of deranged muscle rather than of synaptic processes.

Toxicologic studies in a fatal overdose of 2,4-D, MCPP, and chlorpyrifos.

A death due to ingestion of 2,4-dichlorophenoxyacetic acid (2,4-D), 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP), and phosphorothioic acid O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl)ester (chlorpyrifos) is reported. The clinical course, dose ingested, and plasma levels of the chemicals were compatible with previous fatalities due to the chlorophenoxyacetic acids. Chlorpyrifos concentrations and tissue cholinesterase and in esterase inhibitions indicated the presence of the organophosphate and its biochemical effect, but few cholinergic signs were observed clinically. Lymphocytic neurotoxic esterase activity was decreased for a limited period of time after ingestion. Postmortem nervous tissue neurotoxic esterase was also decreased. This association has not been demonstrated before in man. HPLC and GC/NPD methods for measuring chlorophenoxy acetic acids and chlorpyrifos, respectively, are presented.