AIMSParaquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. METHODSA non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. RESULTSThe paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h −1 , 2.4 l kg −1 and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l −1 caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function.

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We found no evidence that high dose immunosuppression improves survival in paraquat-poisoned patients. The continuing high mortality means further research on the use of dexamethasone and other potential treatments is urgently needed.

Accidental or intentional ingestion of glyphosate surfactant-based herbicides, like Roundup, leads to nephrotoxicity as well as death. In this study, a panel of kidney injury biomarkers was evaluated in terms of suitability to detect acute kidney injury and dysfunction. The Roundup intoxication model involved oral administration of glyphosate to rats at dose levels of 250, 500, 1200 and 2500 mg/kg. Urinary and plasma biomarker patterns were investigated at 8, 24 and 48 hours after dosing.Biomarkers were quantified by absolute concentration; by normalising to urine creatinine; and by calculating the excretion rate. The diagnostic performances of each method in predicting of acute kidney injury were compared. By Receiver Operating Characteristic (ROC) analysis of the selected biomarkers, only urinary kidney injury molecule-1 (KIM-1) best predicted histological changes at 8 h (best cut-off point > 0.00029 µg/ml). Plasma creatinine performed better than other biomarkers at 24 h (best cut-off point > 0.21 mg/dl). Urinary KIM-1 was the best early biomarker of kidney injury in this glyphosate-induced nephrotoxicity model.

Glyphosate herbicide is promoted by the manufacturer as having no risks to human health, with acute toxicity being very low in normal use. In Thailand, however, poisoning from glyphosate agricultural herbicides has been increasing. A case of rapid lethal intoxication from glyphosate-surfactant herbicide involved a 37-year-old woman, who deliberately ingested approximately 500 mL of concentrated Roundup formulation (41% glyphosate as the isopropylamine salt and 15% polyoxyethylene amine; Mosanto Company). The postmortem examination revealed that the stomach contained 550 mL of yellow fluid. The gastric mucosa of anterior fundus revealed hemorrhage and the small intestines had marked dilatation and thin walls. We used the high-performance liquid chromatography method for determination of serum and gastric content levels of glyphosate. The glyphosate levels of serum and gastric content were 3.05 and 59.72 mg/mL, respectively. Toxic effects of polyoxyethylene amine and Roundup were caused by their ability to erode tissues including mucous membranes and linings of the gastrointestinal and respiratory tracts. A mild degree of pulmonary congestion and edema was observed in both lungs. We proposed that the characteristic picture of microvesicular steatosis of the hepatocytes, seen predominantly in centrilobular zones of the liver, resembled drug-induced hepatic toxicity or secondary hypoxic stress.

BackgroundAcute kidney injury (AKI) is common after severe paraquat poisoning and usually heralds a fatal outcome. The rapid large increases in serum creatinine (Cr) exceed that which can be explained by creatinine kinetics based on loss of glomerular filtration rate (GFR).Methods and FindingsThis prospective multi-centre study compared the kinetics of two surrogate markers of GFR, serum creatinine and serum cystatin C (CysC), following paraquat poisoning to understand and assess renal functional loss after paraquat poisoning. Sixty-six acute paraquat poisoning patients admitted to medical units of five hospitals were included. Relative changes in creatinine and CysC were monitored in serial blood and urine samples, and influences of non-renal factors were also studied.ResultsForty-eight of 66 patients developed AKI (AKIN criteria), with 37 (56%) developing moderate to severe AKI (AKIN stage 2 or 3). The 37 patients showed rapid increases in creatinine of >100% within 24 hours, >200% within 48 hours and >300% by 72 hours and 17 of the 37 died. CysC concentration increased by 50% at 24 hours in the same 37 patients and then remained constant. The creatinine/CysC ratio increased 8 fold over 72 hours. There was a modest fall in urinary creatinine and serum/urine creatinine ratios and a moderate increase in urinary paraquat during first three days.ConclusionLoss of renal function contributes modestly to the large increases in creatinine following paraquat poisoning. The rapid rise in serum creatinine most probably represents increased production of creatine and creatinine to meet the energy demand following severe oxidative stress. Minor contributions include increased cyclisation of creatine to creatinine because of acidosis and competitive or non-competitive inhibition of creatinine secretion. Creatinine is not a good marker of renal functional loss after paraquat poisoning and renal injury should be evaluated using more specific biomarkers of renal injury.

Simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods have been developed and validated for quantification of paraquat (PQ) in plasma and urine. Plasma and urine sample preparation were carried out by one-step protein precipitation using cold acetonitrile (-20 to -10 °C). After centrifugation, an aliquot of 10 μL of supernatant was injected into a Kinetex™ hydrophilic interaction chromatography (HILIC) column with a KrudKatcher™ Ultra in-line filter. The chromatographic separation was achieved using the mobile phase mixture of 250 mM ammonium formate (with 0.8% aqueous formic acid) in water and acetonitrile at a flow rate of 0.3 mL/min. Detection was performed using an API2000 triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode via an electrospray ionization (ESI) source. The calibration curve was linear over the concentration range of 10-5000 ng/mL, with an LLOQ of 10 ng/mL. The inter- and intra-day precision (% R.S.D.) were <8.5% and 6.4% for plasma and urine, respectively with the accuracies (%) within the range of 95.1-102.8%. PQ in plasma and urine samples was stable when stored at -70 °C for three freeze-thaw cycles. The methods were successfully applied to determine PQ concentration in rat and human samples.

To elucidate characteristics of gunshot residues in gunshot entry wounds with full-jacketed and lead bullets, element contents in entry gunshot wounds and control skins were analyzed by inductively coupled plasma-atomic emission spectrometry (ICP-AES). It was found that a high content of Fe and Zn was deposited in the gunshot entry wounds with full-jacketed bullet, whereas a high content of Pb was deposited in the gunshot entry wounds with lead (unjacked) bullet. It should be noted that the content of Pb was significantly higher in the gunshot entry wounds with lead bullet than in those with full-jacketed bullet. Regarding the relationships among elements, it was found that there were significant direct correlations between Pb and either Sb or Ba contents in both gunshot entry wounds with full-jacketed and lead bullets. As Pb increased in both gunshot entry wounds, Sb and Ba also increased in the wounds.