Epidemiology and renal injury following 2-methyl-4-chlorophenoxyacetic acid (MCPA) poisoning.

2-Methyl-4-chlorophenoxyacetic acid (MCPA) is a widely used chlorophenoxy herbicide. MCPA poisoning causes mitochondrial dysfunction, which can lead to kidney injury and death. The objective of this study is to describe the epidemiology, case fatality and extent of renal injury in a large cohort of MCPA self-poisonings. The study consists of two parts: (1) A report of epidemiological data and clinical outcomes in MCPA poisoned patients in Sri Lanka between 2002 and 2019; (2) Evaluation of acute kidney injury (AKI) using renal biomarkers in a subset from this cohort. Serum creatinine (sCr) and biomarkers were measured soon after hospitalization (2 [IQR 1-3] h) and at different time intervals. We measured serum biomarkers: sCr, cystatin C (sCysC), creatine kinase (CK), and urinary biomarkers: creatinine, kidney injury molecule-1 (KIM-1), clusterin, albumin, beta-2-microglobulin (ß2M), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), trefoil factor 3 (TFF3) and cytochrome C (CytoC). Kidney Disease Improving Global Outcomes (KDIGO) criteria was used to define acute kidney injury (AKI). There were 1653 patients; 65% were male. The median time from ingestion to examination was 3:54 (IQR 2:19-6:57) h. The overall case-fatality rate was 5.3%. Patients who died were older (42 [IQR 33.5-54] vs 27 [IQR 20-37] for survivors). The median estimated amount of MCPA ingested by patients who died was also greater (88 [IQR 34-200] vs. 30 [IQR 15-63] ml in survivors). Moderate to severe AKI (AKI2/3) was uncommon (6/59 patients in the biomarker study had KDIGO stage 2 or 3). Most patients in AKI2/3 group with increased sCr were older (median age 35 years [IQR 27-41]) compared to No AKI (23 years (19-29) years) or AKI1 (26 years (21-40) years) group who had no or mild increase in sCr. These patients had no pre-existing kidney diseases. In these patients, serum creatinine (maximum medium concentration; 1.12 [IQR 0.93-1.67] mg/dl) and CK (maximum medium concentration; 284 [IQR 94-428] U/l) were increased but sCysC (maximum medium concentration; 0.79 [IQR 0.68-0.81] mg/l) remained in the normal range within 72 h. All urinary biomarkers performed poorly in diagnosing AKI (area under the receiver operating characteristic curve < 0.68). The higher numbers of men with MCPA poisoning likely reflects greater occupational access to pesticides. Fatal outcome and higher ingested dose were more common in the elderly. Significant AKI with tubular injury biomarkers was uncommon. Most people with raised sCr were older and appeared to have no pre-existing kidney disease.

Determination of the phenoxyacid herbicides MCPA, mecoprop and 2,4-D in kidney tissue using liquid chromatography with electrospray tandem mass spectrometry.

An analytical method was developed to determine the phenoxyacid herbicides 2,4-D, MCPA and mecoprop in kidney tissue from animals where poisoning is suspected. Samples were Soxhlet extracted using diethyl ether and the extracts cleaned-up using anion exchange solid phase extraction cartridges. Analysis was performed using liquid chromatography with negative-ion electrospray tandem mass spectrometry (LC-MS/MS). The method was evaluated by analysing control kidney samples fortified at 1 and 5 mg/kg. Mean recoveries ranged from 82 to 93% with relative standard deviations from 3.2 to 19%. The limit of detection was estimated to be 0.02 mg/kg.

A fatal intoxication from ingestion of 2-methyl-4-chlorophenoxyacetic acid (MCPA).

We report a fatal intoxication case by the ingestion of an herbicide, 2-methyl-4-chlorophenoxyacetic acid (MCPA). A 23-year-old male was found dead in his car. The forensic autopsy revealed no remarkable morphological changes. However, in a toxicological screening test, MCPA was qualitatively detected from the extracts of stomach contents. Then MCPA in the extract of each body fluid and organ tissue was determined by gas chromatography-mass spectrometry with trimethylsilyl-derivatization as follows (microg/g): 888.3 in the heart blood, 578.1 in the peripheral blood, 52.2 in the urine, 770.9 in the brain, 1362 in the right lung, 1135 in the liver, 755.5 in the right kidney, and 10,200 in the stomach contents. These data strongly suggested that the male orally ingested MCPA. Moreover, p-chloro-o-cresol (4-chloro-2-methylphenol) was also determined in the body fluids and organ tissues, suggesting a metabolite of MCPA. From these toxicological data, together with autopsy findings, the cause of his death was diagnosed as acute MCPA poisoning.

2-Methyl-4-chlorophenoxyacetic acid (MCPA) and bromoxynil herbicide ingestion.

CONTEXT: Ingestion of bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in combination is associated with high mortality. Toxicity is characterised by hyperthermia and metabolic acidosis. Dialysis is a proposed treatment, but little data exist regarding its effectiveness. CASE DETAILS: Case 1: A 50-year-old female presented 18 h post-ingestion of 200 mL of bromoxynil(200 g/L) and MCPA(200 g/L). She was agitated, tachycardic and tachypnoeic. She was intubated and continuous venovenous haemodiafiltration (CVVHDF) was commenced. She deteriorated, becoming hypotensive, hyperthermic (39.5 °C) and hypercapnic (80 mmHg). She was cooled, paralysed, received CVVHDF for 2d and was extubated on day 4 making a full recovery. Case 2: A 60-year-old male presented 6 h post-ingestion of an unknown amount of bromoxynil (200 g/L) and MCPA (200 g/L). On arrival, he was tachycardic and tachypneic (pCO2 25 mmHg). At 8h post-ingestion he became hyperthermic, hypercapnic and acidotic (pH 7.15), and was intubated, paralysed, cooled and received CVVHDF for 36 h. He was extubated after 42 h and made a full recovery. Bromoxynil and MCPA serum and effluent concentrations were measured. Peak MCPA serum concentrations were 161 µg/ml and 259 µg/ml and peak bromoxynil concentrations were 119 µg/ml and 155 µg/ml in case 1 and 2, respectively. The estimated clearance of both herbicides by CVVHDF was low (<10 mL/min). CONCLUSION: CVVHDF did not result in significant clearance of either herbicide but may have assisted with hyperthermia control. Both patients survived with vigorous cooling, paralysis and ventilatory support.

Urinary alkalinisation for acute chlorophenoxy herbicide poisoning.

BACKGROUND: Acute poisoning with chlorophenoxy herbicides (such as 2,4-D, MCPA, 2,4,5-T and mecoprop) is reported worldwide, potentially causing severe toxicity and death in exposed patients. Animal studies support the application of urinary alkalinisation (particularly using sodium bicarbonate) in the management of acute chlorophenoxy herbicide poisoning to facilitate excretion of these herbicides. Some case reports of human exposure have suggested benefit from urinary alkalinisation also. OBJECTIVES: To assess the efficacy of urinary alkalinisation, in particular sodium bicarbonate, for the treatment of acute chlorophenoxy herbicide poisoning. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CENTRAL, Current Awareness in Clinical Toxicology, Info Trac, http://www.google.com.au, and Science Citation Index of studies identified by the previous searches. The bibliographies of identified articles were reviewed and experts in the field were contacted. SELECTION CRITERIA: Randomised controlled trials of urinary alkalinisation in patients ingesting a chlorophenoxy herbicide and presenting within 24 to 48 hours of poisoning were sought. The quality of studies and eligibility for inclusion was assessed using criteria by Jadad and Schulz. DATA COLLECTION AND ANALYSIS: Authors independently extracted data from the identified studies using a pre-designed form. Study design, including the method of randomisation, participant characteristics, type of intervention and outcomes were all recorded. MAIN RESULTS: No studies were identified which satisfied inclusion criteria. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the routine use of urinary alkalinisation for acute chlorophenoxy herbicide poisoning. A well conducted randomised controlled trial is urgently required to determine whether the efficacy and indications of this treatment.

Direct and indirect effects of the herbicides Glyphosate, Bentazone and MCPA on eelgrass (Zostera marina).

Eelgrass beds are important habitats for many organisms, but there has been a decline in the area covered by eelgrass during the last decades due to increased eutrophication resulting in increased shading from phytoplankton. The use of herbicides in terrestrial agriculture has also increased over the last century, and while the effects of herbicides on non-target organisms have been well studied in freshwater they are overlooked in coastal waters. It is not known if herbicides have any effect on the distribution of eelgrass (Zostera marina), or how natural phytoplankton communities respond to the same herbicides. Direct and indirect effects of the herbicides Glyphosate, Bentazone and MCPA both as single toxicants and as mixtures, on the eelgrass plants were investigated in this study. The direct effects on eelgrass were examined by measuring the four different endpoints; the relatively growth rate as length and weight, the chlorophyll a and b ratio, as well as the RNA-DNA ratio, at the end of a 3 days exposure period. The indirect effect was investigated by measuring the effect on a natural phytoplankton production from Roskilde Fjord six times during 1 year. The results showed that the chlorophyll a-b and RNA-DNA ratios were the most sensitive endpoints in single herbicide experiments. The effects of herbicide mixtures on eelgrass were much larger compared to the single substances. Nearly a halving was found for both the relatively growth rate in length and weight, and the RNA-DNA as well as the chlorophyll a-b ratios were also significant reduced. This indicates a possible synergistic effect, and calculations based on the concentration addition model indicate that the low concentrations mixture has a synergistic effect, whereas the high concentration mixture has an antagonistic effect on eelgrass (Z. marina). The low concentrations mixture is the one with the highest relevance for coastal areas. The effect on phytoplankton showed some variation over the year but mainly in a stimulation in primary production. This means that herbicides affect eelgrass both directly and indirectly.

Intentional self-poisoning with the chlorophenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA).

STUDY OBJECTIVE: Data on poisoning with MCPA (4-chloro-2-methyl-phenoxyacetic acid) are limited to 6 case reports. Our objective is to describe outcomes from intentional self-poisoning with MCPA in a prospective case series of 181 patients presenting to hospitals in Sri Lanka. METHODS: Patient information was collected by on-site study physicians as part of an ongoing prospective cohort study of poisoned patients. Medical history, clinical details, and blood samples were obtained prospectively. RESULTS: Overall clinical toxicity was minimal in 85% of patients, including mild gastrointestinal symptoms in 44% of patients. More severe clinical signs of chlorophenoxy poisoning reported previously, such as rhabdomyolysis, renal dysfunction, and coma, also occurred but were uncommon. Eight patients died (4.4%). Most deaths occurred suddenly from cardiorespiratory arrest within 48 hours of poisoning; the pathophysiological mechanism of death was not apparent. The correlation between admission plasma MCPA concentration and clinical markers of severity of toxicity (physical signs, symptoms, and increased creatine kinase level) was poor. CONCLUSION: Intentional self-poisoning with MCPA generally causes mild toxicity, but cardiorespiratory arrest and death may occur. All patients should receive routine resuscitation and supportive care. It seems reasonable to correct acidosis and maintain an adequate urine output, but there is insufficient evidence to support other specific interventions. Our data do not support a clinical role for measurement of plasma MCPA in the acute management of poisoning, and insufficient data were available to fully examine the utility of measured electrolytes and creatine kinase levels.

2-Methyl-4-chlorophenoxyacetic acid and bromoxynil herbicide death.

CASE REPORT: We report a fatal case of a 37 year old gentleman who ingested a MCPA/bromoxynil co-formulation herbicide. Although clinically well on initial examination, our patient declined dramatically over his 18 h admission with increasing CO2 production, hyperthermia and metabolic derangement to eventually die from cardiac asystole 20 h post ingestion. Two hours after ingestion the MCPA concentration was 83.9 µg/mL and bromoxynil concentration was 137 µg/mL. DISCUSSION: The patients' mechanism of death appeared to be uncoupling of oxidative phosphorylation, excess CO2 production and hyperthermia. There is limited knowledge on the acute toxicity of these herbicides, in particular bromoxynil, and this case highlights the relentless progression of severe toxicity in humans.

Suicidal poisoning by MCPA and parathion.

A suicidal poisoning committed by a sixty-five year old woman, who swallowed a bottle of Agroxyl, containing an aqueous 250 g/L solution of the sodium- and potassium salt of 2-methyl-4-chlorophenoxyacetic acid [MCPA], together with lethal amounts of a parathion formulation, is described. The case history, the postmortem examination and the concentrations of parathion and MCPA in the different viscera, are reported in detail. Parathion determination was performed by means of a routine method, previously developed in our laboratory. The MCPA quantification was achieved using a thoroughly evaluated EC- GLC micro-analytical procedure, which is discussed completely. Identity was confirmed by GC-MS. Intake of lethal parathion quantities caused the woman's death with five minutes. This case however is worth reporting, since we had the unique opportunity to establish the early distribution of MCPA through the body, during the short period of survival.

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.

Toxicologic studies in a fatal overdose of 2,4-D, mecoprop, and dicamba.

A suicidal poisoning committed by a 61-year-old woman, who ingested an unknown quantity of Killex, containing in aqueous solution 100 g/L of (2,4-dichlorophenox)acetic acid (2,4-D), 50 g/L of mecoprop, and 9 g/L of dicamba as amine salts is described. Quantitation of chlorophenoxy acids was performed by extraction from an acidified mixture and concentration before high performance liquid chromatography analysis. All three herbicides were separated in a phosphate buffer/acetonitrile mixture at 280 nm on a RP-8 column. Concentrations of herbicides found were: in blood--520-mg/L 2,4-D, 530-mg/L mecoprop, and 170-mg/L dicamba; in urine--670-mg/L 2,4-D and 520-mg/L mecoprop; in bile--340-mg/L 2,4-D, 530-mg/L mecoprop, and 140-mg/L dicamba; and in liver--540-mg/Kg 2,4-D, 500-mg/Kg mecoprop, and less than 100-mg/Kg dicamba. Liquid chromatography was found to be a reliable method for herbicide quantitation in biological tissues and fluids. The technique offered definite advantages over ultraviolet spectrophotometry and avoids the derivatization requirement for gas chromatography.

Suspected herbicide toxicosis in a dog.

An 8-year-old 38-kg spayed female Golden Retriever was admitted for vomiting, signs of abdominal pain on palpation, ataxia, anorexia, and generalized weakness of 2 days' duration. Ten hours prior to onset of clinical signs, the dog was found standing in and drinking from large pools of an accidentally spilled herbicide that contained an octanoic acid ester of bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and an isooctyl ester of (2-methyl-4-chloro) phenoxyacetic acid (MCPA). Appendicular muscles were firm on palpation and persistent muscle contraction (myotonia > 1 minute duration) was found on muscle percussion, using a reflex hammer. Electrical activity indicative of myotonia was identified on electromyographic evaluation. With supportive treatment, the dog eventually recovered from suspected MCPA toxicosis. Although rare, MCPA toxicosis should be considered as a cause of acquired myotonia in dogs.

Severe polyneuropathy in a 3-year-old child after dichlorophenoxyacetic herbicide--chwastox intoxication, treated successfully with plasmapheresis (PF).

The clinical picture of intoxication with dichlorophenoxy acetic herbicides is well recognised in adults and some treatment recommendations are established. To the best of our knowledge there is scarcity of well documented cases of intoxication with this substance in children. Our report describes the clinical picture of Chwastox intoxication in a 3-year-old child. Some similarities and differences between adults and children are discussed, as well as the indications for plasmapheresis, which could be a valuable mode of treatment in such cases.

An unusual case of non-fatal poisoning due to herbicide 4-chloro-2-methyl phenoxyacetic acid (MCPA).

MCPA (4-chloro-2-methyl phenoxyacetic acid) is a systemic hormone-type selective herbicide readily absorbed by leaves and roots. Use of MCPA for murder or attempted murder is very rare in Sri Lanka. However, a reported case of attempted murder by adding MCPA to water will be discussed in this paper. Three extraction methods were carried out with urine samples spiked with MCPA, namely liquid-liquid extraction with chloroform, solid phase extraction using C18 cartridges and vortex mixing with methanolic hydrochloric acid. Based on the recovery results, solid phase extraction was selected as the most suitable method and applied in the analysis of urine and water samples. Identification of MCPA in urine, water and the suspected poison bottle was carried out by HPLC and was confirmed by GC-MS. 4-chloro -2- methyl phenol metabolite was also identified and confirmed in the urine sample of the patient by GC-MS. Quantitative analysis of MCPA was carried out by HPLC using a validated method where Zorbax XDB-C18 column was used with photo diode array detector. In this case, presence of MCPA in one patient's urine sample collected four days after the incident was confirmed by GC-MS and found at a concentration of 0.83µg/ml. MCPA was not identified in the urine samples collected after 13 days in other three patients. The water sample taken from the suspected water storage tank found to contain 101µg/ml of MCPA. The results showed that HPLC combined with GC-MS is suitable for forensic analysis of MCPA in urine.

Triketone toxicity: a report on two cases of sulcotrione poisoning.

INTRODUCTION: Sulcotrione is a herbicidal agent belonging to the family of triketones. Sulcotrione herbicides are used for weed control in maize and flax crops. To date, no cases of human poisoning had been reported in the literature linked to different herbicidal agents in the triketone family. We report here on two cases of the voluntary ingestion of this substance in the form of the branded product Mikado(TM), which were recorded by the Angers Poison Centre. CASE REPORT: Both cases of voluntary ingestion constituted attempted suicide, and involved two men aged 30 and 37 years. Their symptoms linked to sulcotrione were limited to vomiting, despite elevated plasma concentrations of sulcotrione. In one case, hypertyrosinemia has been demonstrated. The outcome was favourable in both patients and at follow up, no ocular disorders were observed. In the second case, hypotension and transient renal failure could be linked to the concomitant ingestion of chlorophenoxy herbicides. DISCUSSION: In animal toxicity studies, sulcotrione inhibit 4-hydro-phenylpyruvate dioxygenase leading to hypertyrosinemia and corneal opacities. In both cases, no ocular disorders were observed despite hypertyrosinemia in one case. These case reports were consistent with the animal toxicology findings concerning triketones, and particularly their relative safety in mammals following acute poisoning. However it seems prudent to monitor plasma tyrosine concentrations and to screen prospectively for corneal deposits if further acute intoxication events occur.

Toxicokinetics, including saturable protein binding, of 4-chloro-2-methyl phenoxyacetic acid (MCPA) in patients with acute poisoning.

Human data on protein binding and dose-dependent changes in toxicokinetics for MCPA are very limited. 128 blood samples were obtained in 49 patients with acute MCPA poisoning and total and unbound concentrations of MCPA were determined. The Scatchard plot was biphasic suggesting protein binding to two sites. The free MCPA concentration increased when the total concentration exceeded 239mg/L (95% confidence interval 198-274mg/L). Nonlinear regression using a two-site binding hyperbola model estimated saturation of the high affinity binding site at 115mg/L (95%CI 0-304). Further analyses using global fitting of serial data and adjusting for the concentration of albumin predicted similar concentrations for saturable binding (184mg/L and 167mg/L, respectively) without narrowing the 95%CI. In 25 patients, the plasma concentration-time curves for both bound and unbound MCPA were approximately log-linear which may suggest first order elimination, although sampling was infrequent so zero order elimination cannot be excluded. Using a cut-off concentration of 200mg/L, the half-life of MCPA at higher concentrations was 25.5h (95%CI 15.0-83.0h; n=16 patients) compared to 16.8h (95%CI 13.6-22.2h; n=10 patients) at lower concentrations. MCPA is subject to saturable protein binding but the influence on half-life appears marginal.

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.