Liquid chromatography with tandem mass spectrometry for the determination of flufenoxuron in blood using automatic solid phase extraction and its application to a fatal case of flufenoxuron poisoning.

A liquid chromatography/tandem mass spectrometry method with solid phase extraction for the detection and the quantitation of flufenoxuron in an aliquot of blood was developed and validated. Flufenoxuron belongs to a benzoylurea insecticide and is the active ingredient of Cascade™. The analyte in postmortem specimens was extracted by solid-phase extraction with Bond Elut Certify cartridge. After the elution layer was evaporated, the residue was reconstituted with 70% methanol for LC/MS/MS analysis. Separations were carried out on a Synergi(®) 2.5u Fusion-RP 100 A column with column temperature kept at 40 °C at a flow rate of 0.4 mL/min. The mobile phase was composed of 5mM ammonium formate in 10% methanol and 5 mM ammonium formate in 90% methanol using gradient elution. A triple quadruple mass spectrometer equipped with an electrospray ionization source operated in a positive ion mode with selective reaction monitoring mode. Atrazine-d5 was used as internal standard. The assay was linear over 0.02-1.0 mg/L (r(2)=0.999). Limit of detection (LOD) and limit of quantitation (LOQ) in blood were 0.009 mg/L (S/N=3) and 0.02 mg/L (S/N=10), respectively. The accuracy and the precision were <14.9% of bias% and <8.1% of CV%, which are acceptable criteria according to toxicology laboratory guidelines. Relative recoveries with 0.02, 0.1 and 1.0mg/L (in blood) were 112.3%, 101.2% and 111.0% (n=5), respectively. The developed method was applied in forensic toxicology to determine flufenoxuron in postmortem specimens in a fatal case of flufenoxuron intoxication in a 48-year-old-man who was found dead on bed in a small room after vomiting on the floor. The postmortem heart blood, peripheral blood and gastric contents were analyzed for flufenoxuron with the result of 6.3 mg/L in heart blood, 3.2 mg/L in peripheral blood and 30.6 mg/kg in gastric contents, respectively. The concentration ratio of the heart/peripheral blood of flufenoxuron was 2.0, and the ratio of gastric contents/peripheral blood was 9.4, suggesting possible postmortem redistribution and there may be a massive amount of flufenoxuron orally ingested. This case study is the first report of lethal concentrations of flufenoxuron in postmortem specimens.

Severe human poisoning with a flufenoxuron-containing insecticide: Report of a case with transient myocardial dysfunction and review of the literature.

CONTEXT: Flufenoxuron (Cascade™) is a new benzoylurea insecticide. We describe a case of human poisoning with previously unreported cardiac complications and review other case reports in the literature. CASE DETAILS: A 54-year-old stuporous man who had ingested a flufenoxuron-containing insecticide presented to the emergency department with severely unstable vital signs and lactic acidosis which continued to worsen over time. He was treated with gastric lavage and infusion of sodium bicarbonate, crystalloid, and dopamine. The patient was initially unresponsive, but recovered from shock after norepinephrine treatment. While electrocardiography showed no abnormal findings, cardiac enzymes remained elevated for several days. Initial echocardiography showed global left ventricular hypokinesia and a left ventricular ejection fraction of 40%, but echocardiography after 45 h showed normal results. On the sixth day, he was discharged after rejecting medical advice for further evaluation. DISCUSSION: Severe lactic acidosis, shock, elevation of cardiac enzymes, and global left ventricular hypokinesia can occur in human poisoning with flufenoxuron-containing insecticide, and norepinephrine is preferable for the management of shock.

Worker illness related to newly marketed pesticides--Douglas County, Washington, 2014.

On April 10, 2014 the Washington State Department of Agriculture (WSDA) was notified by a local newspaper of a suspected pesticide poisoning incident in Douglas County involving pesticides not previously reported in the published literature to be associated with human illness. On that same day, WSDA notified the Washington State Department of Health, which investigated this incident by conducting a site visit, reviewing medical and applicator records, and interviewing affected farmworkers, pesticide applicators, and the farmworkers' employer. In addition, on April 11, WSDA collected swab, foliage, and clothing samples and tested them for residues of pyridaben, novaluron, and triflumizole. In this incident, all 20 farmworkers working in a cherry orchard became ill from off-target drift of a pesticide mixture that was being applied to a neighboring pear orchard. Sixteen sought medical treatment for neurologic, gastrointestinal, ocular, and respiratory symptoms. This event highlights the need for greater efforts to prevent off-target drift exposures and promote awareness about the toxicity of some recently marketed pesticides. Incidents such as this could be prevented if farm managers planning pesticide applications notify their neighbors of their plans.

A case of human poisoning with a flufenoxuron-containing insecticide.

INTRODUCTION: Flufenoxuron is a recently introduced insecticide. The compound is known to exert its insecticidal activity by inhibiting chitin synthesis in insects. However, its toxic effects on humans are unknown. CASE REPORT: A 72-year-old woman was brought to the emergency department by ambulance. The person accompanying her brought an empty 100-mL bottle of an insecticide (Cascade), which was found at the scene. The active ingredient of the product is flufenoxuron and the other components include surfactants and solvents. A detailed composition obtained from the manufacturer was flufenoxuron, ethoxylated nonylphenol phosphate, polyoxyethylene nonylphenol, N-methyl-2-pyrrolidone, and cyclohexanone. Upon arrival at the intensive care unit (ICU), her arterial pH was 7.093, her bicarbonate level was 7.4 mEq/L, and the anion gap was 33.8 mEq/L. Her lactic acid concentration was 16.5 mmol/L. Lactic acidosis was not considered to be a consequence of circulatory shock, because there was no clinical sign of shock other than lactic acidosis, and cardiac output was never below 4.5 L/min. Her acid-base status began to improve and returned to near normal on the next day. CONCLUSION: It can be hypothesized that the toxicity of the product includes inhibition of the oxygen utilization mechanism at the cellular level. The product is composed of a number of components, similar to many other herbicide products. It is not possible to identify which of the ingredients was specifically responsible for the toxic effects in this case.

Poisoning due to urea herbicides.

Urea herbicides, which act by inhibiting photosynthesis, were introduced in 1952 and are now used as pre- and post-emergence herbicides for general weed control in agricultural and non-agricultural practices. Urea herbicides are generally of low acute toxicity and severe poisoning is only likely following ingestion when nausea, vomiting, diarrhoea and abdominal pain may occur. As urea herbicides are metabolised to aniline derivatives, which are potent oxidants of haemoglobin, methaemoglobinaemia (18-80%) has been documented, as well as haemolysis. Treatment is supportive and symptomatic. Methylthioninium chloride (methylene blue) 1-2mg (the dose depending on the severity of features) should be administered intravenously over 5-10 minutes if there are symptoms consistent with methaemoglobinaemia and/or a methaemoglobin concentration >30%.

Acute metobromuron poisoning with severe associated methemoglobinemia. Identification of four metabolites in plasma and urine by LC-DAD, LC-ESI-MS, and LC-ESI-MS-MS.

A case of self poisoning with metobromuron, a urea derivative used as a herbicide, is reported. Severe methemoglobinemia observed at the admission (80%) disappeared only at day 11, and hemolysis appeared at day 4 and decreased slowly to day 12. Metobromuron was analyzed by liquid chromatography with diode-array detection. Initial plasma concentration and elimination half-life were 4.9 mg/L and 5 h, respectively. Several metabolites were also detected, and four of those were identified by liquid chromatography-electrospray mass spectrometry. Normetobromuron, bromophenylurea, and bromoacetanilide were detected in plasma, but only N-methyl bromophenylurea was detected in urine. Bromoacetanilide probably results from acetylation of the intermediate bromoaniline. Methemoglobinemia could result from metabolization of metobromuron to bromoaniline and bromoacetanilide.

[Methemoglobinemia caused by accidental poisoning with metolachlor and metobromuron]. / Methemoglobinemija uzrokovana akcidentalnom intoksikacijom metolaklorom i metobromuronom.

An 81-year-old man was admitted in the emergency department approximately four hours after accidental, ingestion of an unknown quantity of herbicide "Galex 500 EC". This product contains 25% of metolachlor and 25% of metobromuron dissolved in xylene. In spite of the fact that the combination of aniline and urea-substituted derivatives is widely used in agriculture as herbicide, there are very few data available about their harmful effects on humans. These agents appear to be mildly toxic, and rarely has a major systemic effect been reported after the poisoning. On admittance, our patient showed remarkable cyanosis and his methaemoglobin level was 38.4% of the total haemoglobin, rising next day to 46.2%. Only mild transient signs of hypoxic effects on central nervous system were observed and the laboratory findings indicated mild haemolysis. Methylene blue was applied intravenously in a dose of 1.5 mg/kg (10 ml, 1% solution) on the second day of admission. Administration of methylene blue was very effective and the patient was discharged from the hospital fully recovered.

Inhibition of mitochondrial complex I may account for IDDM induced by intoxication with the rodenticide Vacor.

Human intoxication with the rodenticide Vacor [N-3-pyridylmethyl-N'-p-nitrophenyl urea or 1-(4-nitrophenyl)-3-(3-pyridylmethyl) urea] induces acute IDDM. We report here that Vacor specifically inhibits the NADH:ubiquinone reductase activity of complex I in mammalian mitochondria. The activity of other respiratory enzymes of mitochondria is unaffected by Vacor at concentrations that completely inhibit the redox and energetic function of complex I. Vacor inhibition of complex I activity quantitatively correlates with the inhibition of insulin release in insulinoma cells and pancreatic islets and is also consistent with the doses reported in cases of human poisoning. These results indicate that the toxic and diabetogenic action of Vacor primarily derives from the inhibition of mitochondrial respiration of NAD-linked substrates in the high-energy demanding cells of the pancreatic islets. This newly identified mechanism of the pathological effects resulting from Vacor intoxication could constitute a paradigm in which to understand environmental or metabolic causes of IDDM.

Metobromuron/metolachlor ingestion with late onset methemoglobinemia in a pregnant woman successfully treated with methylene blue.

Metobromuron, a substituted urea herbicide, is widely used for control of grasses and broad-leaved weeds in Taiwan. Major systemic toxicity has not been reported following poisoning. A 22-year-old woman at 36 weeks of gestation was admitted to the emergency department three hours after ingestion of a mixture of 25% metobromuron and 25% metolachlor. Though stable initially, she developed central cyanosis 12 hours later. Emergent cesarean section was considered but administration of intravenous methylene blue readily reversed the cyanosis and prevented the operation. Recurrent cyanosis did not develop. Normal vaginal delivery occurred 17 days after the poisoning. Follow-up for four years revealed normal growth of the child. Metobromuron poisoning, like other urea herbicides, may cause methemoglobinemia via its hydrolysis products. Administration of methylene blue is effective treatment and should be considered in the treatment of methemoglobinemia following urea herbicide poisoning.

[The setting of hygienic standards for the insecticide sonet in potatoes]. / Gigienicheskoe normirovanie insektitsida sonet v kartofele.

A study of the toxic properties of sonet in chronic experiment on white rats established the threshold and non-acting dose of the insecticide. The accumulation of the insecticide in the potato tubers during the entire vegetation period as well as its effect on the potato quality were investigated. The author recommends 0.05 mg/g of sonet per 1 g of potato as a maximum permissible level.

N-3-pyridylmethyl-N'-p-nitrophenylurea ocular toxicity in man and rabbits.

Ingestion of the rat poison N-3-pyridylmethyl-N'-p-nitrophenylurea (PNU) produced ocular toxicity in three humans and in an animal model, the Dutch Belted rabbit. The electroretinogram b wave was especially susceptible to the effects of the rodenticide, and the target tissue appeared to be the retinal pigment epithelium. Injection of PNU itself did not produce ocular toxicity. The poison had to be administered orally. Gentamicin administered orally with PNU prevented the ocular toxicity. Presumably this antibiotic killed those gastrointestinal bacteria responsible for PNU's metabolism into an ocular toxin. L-tryptophan, a known antidote for the lethal effects of PNU, was an antidote for the ocular toxicity when administered orally but not when administered parenterally.

[Burning feet caused by the rodenticide RH-787]. / Brennende Füsse, verursacht durch Rattengift RH-787.

Four patients developed severe burning feet after ingestion of the rodenticide RH-787 (Vaccor-B) attempting suicide. Parenteral administration of vitamin-B-complex relieved the symptom in all patients. Based on the results of these four patients and other data in the literature, vitamin-B-deficiency is discussed as a possible cause of burning feet.

Effects of packaging and appearance on childhood poisoning. Vacor rat poison.

Over a 13-month period, 14 patients were hospitalized at Milwaukee Children's Hospital for rodenticide ingestions. Ten of the 14 patients ingested Vacor Rat Poison (N-3-pyridylmethyl N'-p-nitrophenyl urea). Small children could easily mistake Vacor, which resembles corn meal, for breakfast cereal. To intervene for safer packaging of toxic substances, pediatricians need to be aware of the health hazard posed to children by attractive packaging.

Full recovery from severe orthostatic hypotension after vacor rodenticide ingestion.

A patient who had severe orthostatic hypotension secondary to ingesting Vacor, a rodenticide containing N-3 pyridilmethyl-N'-nitrophenyl urea (PNU), fully recovered from this initially disabling condition 11 months after poisoning. Initial treatments with elastic stockings, fludrocortisone acetate, and dihydroergotamine mesylate resulted in no obvious improvement of his orthostasis. Findings from a hemodynamic study performed with the patient was severely orthostatic suggested functional impairment of vascular adrenergic nerve terminals as a major lesion. A similar study after recovery from orthostasis showed that the baroreceptor reflex mechanism returned to normal. This report shows that initially severe and disabling orthostatic hypotension may not be a hopelessly permanent sequela of PNU intoxication and that a gradual, spontaneous full recovery from orthostasis is possible.