Toxicity of tetramethylammonium hydroxide: review of two fatal cases of dermal exposure and development of an animal model.

To document two cases of patients who were fatally exposed to tetramethylammonium hydroxide (TMAH) on the skin and to establish a rat model to investigate the effects of dermal exposure to TMAH. The charts of two workers who died from occupational accidental exposure to TMAH were reviewed. The 4-hour lethal dose (LD50) of TMAH was determined by applying solutions mimicking the two most common industrially used concentrations (2.38% and 25%) of TMAH to the skin of Sprague-Dawley rats. Exposure of the rat's skin to 2.38% or 25% TMAH generated LD50 values of 85.9 mg/kg and 28.7 mg/kg, respectively. Application of either concentration of TMAH to the skin produced a rapid, significant increase in the rate of respiration. The serum concentrations of tetramethylammonium (TMA) also changed significantly with time of exposure to both concentrations of TMAH. The level of blood urea nitrogen decreased significantly in rats exposed to the 2.38% TMAH, and rats exposed to the 25% solution had a significant decrease in the serum concentration of sodium. Injection of atropine after 5 minutes of exposure did not significantly overcome any of the toxic effects observed with either solution of TMAH. The preliminary results in the rat model indicated that the lethality of TMAH cannot be fully explained by the severity of the patients' chemical burns, and the physiologic effects on respiratory and kidney functions were probably involved.

Treatment of Ventricular Fibrillation Due to Ammonium Bifluoride Poisoning With Hemodialysis.

Ammonium bifluoride is an inorganic, fluoride-containing compound found in glass and metal etching products, as well as wheel cleaners. Fluoride toxicity is a common cause of preventable poisoning and has been reported to cause life-threatening ventricular dysrhythmias. Here, we report a case of recurrent ventricular fibrillation secondary to ingestion of ammonium bifluoride. The patient presented with vomiting and coma. She was intubated for altered mental status and respiratory failure and subsequently had 5 episodes of ventricular fibrillation, each resolving with a single defibrillation. She developed metabolic acidosis and hypocalcemia, which were treated with sodium bicarbonate and calcium gluconate, respectively. During transfer to a tertiary care children's hospital, ventricular fibrillation recurred despite electrolyte correction. Hemodialysis (HD) was initiated emergently. No further dysrhythmia occurred after initiation of HD. The result of a basic urine drug screen was negative, and a comprehensive drug screen (gas chromatography and mass spectroscopy) revealed only a nonsignificant peak for diphenhydramine. Subsequent laboratory evaluation revealed an elevated serum fluoride level. Diagnostic laryngoscopy and upper endoscopy did not reveal evidence of caustic injury. She was successfully extubated on hospital day 2 and discharged from the hospital on day 4 with no neurologic sequelae. With this example, we demonstrate a potential therapeutic approach to this potentially lethal poisoning. Fluoride toxicity is typically treated with calcium. However, dysrhythmia may result from calcium-independent direct myocardial toxicity. The kinetics of fluoride are amenable to HD, and renal clearance is slow. The potential use of HD in cases of fluoride poisoning refractory to other therapies warrants further study.

The tissue distribution of fluoride in a fatal case of self-poisoning.

The purpose of this paper is to report a case of fluoride poisoning along with a discussion of poisoning characteristics, analytical procedures, and a review of previous reports of fatal intoxications with analytical data. A case of suicidal ingestion of 40 mL of a rust removal agent containing hydrofluoric acid and ammonium fluoride by a 33-year-old white male is presented. He had an organic personality disorder with residual schizophrenia and previous suicide attempts with therapeutic drugs and cleaning products. At admission, he presented with a Glasgow coma score of 3, third degree atrioventricular block, and asystole. Resuscitation efforts were performed during which the patient suffered two episodes of ventricular fibrillation followed by asystole. In spite of advanced resuscitation efforts and the administration of calcium chloride, he died 2.5 h after the ingestion. Analytical data in the hospital showed calcium levels of 3.1 mg/dL and metabolic acidosis. Internal findings were erosive gastritis, brain edema, and pulmonary and hepatic congestion. Quantitation of fluoride was performed using an ion-selective electrode for the anion. Disposition of fluoride in the different tissues was as follows: peripheral blood, 19.4 mg/L; urine, 670 mg/L; vitreous humor, 2.5 mg/L; liver, 40.0 mg/kg; kidney, 60.0 mg/kg; lung, 17.5 mg/kg; brain, 2.5 mg/kg; spleen, 30.0 mg/kg; bone, 0.5 mg/ kg; and gastric content, 1120 mg/L (67 mg total). Validation of the analytical method was performed using different spiked tissues, in a range of concentrations from 2.4 to 475 mg/L or mg/kg, and submitting them to dilution (1:25) to avoid the matrix effect and to bring these concentrations to the range of the aqueous calibration curve (0.19-19 mg/L). Limits of detection and quantitation were 0.02 and 0.1 mg/L, respectively. The linearity of the method, for all studies tissues, was excellent, with r(2) values of 0.999. Accuracy and precision were within 10.5% and 5.7%, respectively. Fluoride analyses using the ion selective electrode are simple, sensitive, and rapid. This report provides an extensive tissue distribution study of fluoride after a well documented case of acute poisoning. Based on the autopsy findings, patient history, toxicology results, and previously reported data the forensic pathologists ruled that the cause of death was due to a fluoride poisoning, and the manner of death was listed as suicide.

Lethal cardiotoxicity from quaternary ammonium compounds contained in an unguarded household detergent at a psychiatric facility.

Here, referred for the first time in literature, we present the forensic case of death, with suicidal intent, following ingestion of a conspicuous amount of quaternary ammonium compounds contained in an unguarded bottle of household detergent. The deceased person was a young female patient at a psychiatric facility; the cause of death was acute heart failure due to spotty infiltration of neutrophils, lymphocytes and plasma cells in the myocardial tissue, observable in the course of toxic myocarditis. The dominant pathogenetic factors involved are direct damage of myocardial cells and a superimposed immune response extending to the epicardial perivascular spaces. This rare form of acute myocarditis has never been previously described. Moreover, this fatal event emphasizes the need for planned clinical risk-management measures and for guidelines to prevent future adverse events of this kind in psychiatric facilities.

Effects of glutamate and sulphur containing amino acids on ammonia toxicity and methionine sulphoximine convulsions in mice.

Arginine and large doses of glutamate (greater than 500 mg/kg) were found to reduce ammonia toxicity transiently in mice. Smaller doses of glutamate (greater than or equal to 200 mg/kg) were effective when administered with glucose. Cysteic acid, homocysteine and methionine, but not taurine reduced ammonia toxicity. All 4 amino acids reduced the number of convulsions induced by methionine sulphoximine. It is proposed that taurine has a general anticonvulsant action and that cysteic acid, homocysteine and methionine may have a specific effect on the action of ammonia on the central nervous system.

Oregon's Toxic Household Products Law.

In 1991, Oregon became the first state in the U.S. to require the addition of an aversive agent to ethylene glycol-containing antifreeze and methanol-containing windshield wiper fluid. This new law, entitled "Toxic Household Products (THP) Act," was designed to reduce pediatric and animal poisonings from accidental ingestion of these two potentially lethal consumer automotive products. While not the stated intention of the law, addition of aversive agents to consumer automotive products could also reduce adult poisonings associated with intentional (suicides or alcoholics ingesting methanol-containing windshield wiper fluid) or accidental exposures. This law went into effect April 30, 1995, following settlement of a lawsuit brought by the Chemical Manufacturing Specialties Association (CSMA), a trade group representing the five largest manufacturers of ethylene glycol-based antifreeze in the U.S. This paper discusses the major policy issues that arose following the passage of Oregon's THP Act. Major provisions of the law are provided along with a discussion of CSMA's opposition to the Act's implementation. A description of the eventual settlement that was reached with CSMA as well as the major components of Oregon Health Division's (OHD) enforcement program are also highlighted. Data are presented for 1987 through 1998 on the number of exposures and severity of effects for pediatric cases (children < 6 years old) following exposure to both of these potentially lethal automotive products. However, because of the low incidence of exposures each year, these data are insufficient to draw any conclusions on the impact of the THP Act.

Sudden death following accidental ingestion of chlormequat.

A 59-year-old white male accidentally ingested a mouthful of a plant growth chemical, Cycocel, containing 11.8% of the active ingredient (2-chloroethyl)trimethylammonium chloride (chlormequat). He was seen by a family physician and then transferred to a hospital where he died as a result of ventricular fibrillation, which progressed to asystole. Postingestion symptoms were typical of cholinergic crisis and included salivation, diaphoresis, bradycardia, visual disturbances, and seizure. Autopsy findings showed marked pulmonary edema, coronary atherosclerosis, atheromata of aorta, and localized adenocarcinoma of the prostate. Toxicological analyses of biological samples showed the presence of chlormequat in the stomach contents and urine.

Blood investigation in a fatality involving the veterinary drug T-61.

A case involving an acute fatality resulting from self-administration of about 30 mL of T-61, a euthanasia solution, consisting of a mixture of embutramide, mebezonium, and tetracaine, in a 58-year-old veterinarian is presented. Forensic investigations consisted of an external body examination, during which 5 mL of fluorinated femoral blood was collected. Embutramide and tetracaine were quantitated using gas chromatography coupled to mass spectrometry after extraction with chloroform/isopropanol/n-heptane (50:17:33, v/v) at pH 9.5 and separation on an HP5-MS capillary column. Mebezonium was quantitated using liquid chromatography coupled to mass spectrometry after ion-pair extraction (saturated KI solution) with methylene chloride at pH 5.4 and separation on a 5-mm Nucleosil C18 column. Blood concentrations were 43.0, 6.5, and 0.21 mg/L for embutramide, mebezonium, and tetracaine, respectively. No other drugs, including ethanol, were detected.

A rapid and sensitive high-performance liquid chromatography method for determination of embutramide (a Tanax or T61 component) in human blood with photodiode-array UV detection.

Tanax or T61 is an euthanasia solution commonly used in veterinary medicine. Embutramide is one of the three components. In accidental intoxication, suicide, or suicide attempt, the determination of embutramide is needed to confirm the hypothesis of intoxication. Because the amount of sample is sometimes limited in forensic cases, a new rapid and sensitive high-performance liquid chromatography method using only 0.1 mL of blood has been developed with liquid-liquid extraction. The eluate was monitored with a photodiode-array detector with a fixed wavelength at 273 nm. The method provided extraction recoveries greater than 83%. The detection limit was 0.2 mg/L, and the limit of quantitation was 0.6 mg/L. The linearity of standards was excellent (r > 0.997). Intra- and interday precisions were acceptable with a coefficient of variation

Hepatotoxicity of N, N-dimethylformamide (DMF) in acute poisoning with the veterinary euthanasia drug T-61.

1. We report on a patient who was resuscitated after a suicide attempt with the veterinary euthanasia product T-61 and treated with N-acetylcysteine (NAC) to prevent hepatotoxicity from N,N-dimethylformamide (DMF), the solvent of T-61. 2. Serum concentrations of DMF were high as compared with values published on occupational exposure. 3. The patient showed only a transient increase in liver enzymes with eventually a full recovery. 4. The hepatoprotective effect of NAC was studied in a rat model using the rise in serum sorbitol dehydrogenase (SDH) as a marker for DMF-induced hepatotoxicity. 5. Four series of randomized, controlled and double-blind experiments were carried out and consistently showed a lower increase in SDH in NAC-treated animals in each series. The difference was statistically significant only when the data of the 4 series were pooled. This is probably due to the large interindividual variations in the effect of DMF. 6. We hypothesize that in the rat NAC may have a protective effect. Whether NAC is also protective in patients, in which it is administered after exposure to DMF, cannot be concluded from the present experiments.

[Ventricular tachycardia secondary to phenylpropanolamine poisoning: apropos a case]. / Taquicardia ventricular secundaria a intoxicación por fenilpropanolamina: a propósito de un caso.

We report a case of a 17-years-old patient with an accidental ingestion of high doses of phenylpropanolamine. Nine hours after the ingestion she presented ventricular bigeminy and an episode of non sustained ventricular tachycardia. No cardiovascular disease was demonstrated.

[Poisoning with ammonium tetraformiate--a substance used in silage formation]. / Een intoxicatie met ammoniumtetraformiaat--een hulpstof bij het inkuilen van veevoer.

The case is reported of a 23-year-old man, working in agriculture, who was exposed to the silage additive ammonium tetraformiate, a strong acid. While pumping the fluid some of the substance entered his mouth and was swallowed. He vomited and developed transient dyspnoea. On admission he appeared acidotic, with haemolysis and haemoglobinuria. Lesions on the soft palate and in the oesophagus were observed, and a pulmonary infiltrate developed. Information on the substance was initially not available. Labeling appeared incomplete and misleading. Optimal treatment was delayed.

Aversiveness of denatonium saccharide and quinine in grasshopper mice Onychomys leukogaster.

The responses toward denatonium saccharide and quinine by three rodent species differ from those exhibited by humans. This study measured the relative aversiveness of these two compounds in grasshopper mice (Onychomys leucogaster) to determine if this species responded similarly to or differently from these other rodents. In a choice test, the mice clearly preferred quinine over denatonium saccharide at concentrations of 1/10,000 and 1/50,000, but only marginally preferred quinine at a concentration of 1/1000. When denatonium or quinine was paired with toxicosis, both suppressed drinking at concentrations from 1/10,000 to 1/50,000, but only denatonium suppressed drinking at 1/100,000. Neither compound suppressed drinking at 1 part in million. Grasshopper mice perceived denatonium saccharide as more aversive than quinine in both experiments. Such a response resembled the behavior of humans more than that of the other three rodents previously tested.

Tetramethylammonium hydroxide poisoning during a pallet cleaning demonstration.

OBJECTIVES: The purpose of this study was to examine the cause of an accidental death from acute poisoning resulting from exposure to a cleaner containing tetramethylammonium hydroxide (TMAH) and to consider measures to prevent future cases. METHODS: The authors examined the details and the reason for the accidental death from acute poisoning based on the autopsy report. RESULTS: The victim was a 39-year-old male researcher with 7 years of work experience employed by a surfactant production company. The accident occurred when he was conducting a field test of a newly developed cleaner, containing 8.75% TMAH solution. The researcher spilled the cleaner on his work clothes in the area of both the hands/arms and legs. He was unconscious when discovered. An autopsy found no damage or injury that could have resulted in death other than burns to 12% of his body, and the cause of death was found to be acute poisoning by TMAH. DISCUSSION: TMAH is widely used in the electronics industry as a developer or cleaner. It is a dangerous material, causing neurotoxicity leading to respiratory failure by ganglion block that occurs through skin absorption, and no antidote has been developed yet. For this reason, it is best to completely prevent exposure by wearing proper personal protective equipment. Despite this fatal toxicity of TMAH, it is not classified in Korea as a "chemical requiring legal control". For this reason, it is urgent to raise awareness of the toxic properties of TMAH to prevent additional cases of TMAH poisoning

Distribution of embutramide and mebezonium iodide in a suicide after tanax injection.

Tanax is a veterinary formulation for euthanasia comprising embutramide, mebezonium iodide and tetracaine. A 37-year-old female was found dead on her bed, with three empty used syringes and a bottle of Tanax beside her body. Three needle puncture marks were observed on the body. The aim of this study was to evaluate the distribution of embutramide and mebezonium iodide in different biological matrices (femoral and cardiac blood, liver, muscle and vitreous humor) using a chromatographic method for the simultaneous determination of the two drugs. A direct and sensitive liquid chromatography-tandem mass spectrometry method was developed in multiple reaction monitoring mode with positive ionization. Lidocaine was used as an internal standard. Limits of detection and quantitation of 0.01 and 0.05 mg/L, respectively, were reached for both compounds. Embutramide levels ranged from 2.74 mg/L in vitreous humor to 5.06 mg/L in femoral blood, while mebezonium iodide was found at widely differing concentrations (ranging from 2.80 mg/kg in muscle to 24.80 mg/kg in liver). The chromatographic method developed for this study provides a very simple and sensitive means for the simultaneous determination of embutramide and mebezonium iodide, the emetic concentrations of which were consistent with suicides reported in the literature.

Dimethylformamide metabolism following self-harm using a veterinary euthanasia product.

BACKGROUND: A veterinary euthanasia drug containing embutramide, mebezonium, tetracaine, and dimethylformamide (DMF; T-61® or Tanax®) may cause serious manifestations or even fatalities after self-poisoning. Immediate toxicity is mainly due to a general anesthetic and due to a neuromuscular blocking agent, while delayed hepatotoxicity seems related to the solvent DMF. The protective role of N-acetylcysteine (NAC) administration remains debatable. MATERIAL AND METHODS: Two male veterinarians (50- and 44-year-old) attempted suicide by injecting T-61 in the precordial area for the first one, and by ingesting 50 mL for the second. Both received NAC (for 14 days in the first case and only for 20 h in the second). Urine was collected for the serial determination of DMF, N-methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC). RESULTS: Both patients developed only mild signs of liver injury. The metabolite of DMF, NMF, appeared rapidly in the urine, while a further delay was necessary for AMCC excretion. The kinetics of elimination of DMF and DMF metabolites were slightly slower than those reported in exposed workers. CONCLUSIONS: While both patients had a favorable outcome, there is no clear evidence that NAC could directly influence NMF and AMCC excretion. Further investigations of NMF and AMCC excretion, with and without NAC, would be indicated.

Tetramethylammonium hydroxide poisoning.

INTRODUCTION: Tetramethylammonium hydroxide (TMAH) is widely used as a developer or etchant in semiconductor and photoelectric industries. In addition to alkalinity-related chemical burn, dermal exposure to TMAH may also result in respiratory failure and/or sudden death. The latter toxic effect has been of great concern in Taiwan after the occurrence of three fatalities in recent years. To better understand the toxicity following dermal exposure to TMAH, we analyzed all cases with TMAH exposure reported to the Taiwan Poison Control Center (PCC-Taiwan). CASE REPORTS: In total, there were 13 cases of such exposure, including three patients who died after being exposed to 25% TMAH. A worker also developed severe effects manifesting muscle weakness, dyspnea, hyperglycemia, and chemical burn (28% of total body surface area) shortly after an accidental exposure to 2.38% TMAH. He received endotracheal intubation with assisted ventilation for 2 days and survived. CONCLUSION: Skin corrosive injury related to the alkalinity of TMAH and the ganglionic toxicity of tetramethylammonium ion might contribute to the clinical manifestations that occurred after dermal TMAH exposure. Thorough skin decontamination followed by prompt respiratory support should be the mainstay in the management of dermal TMAH exposure. Preventive strategies are warranted as well to decrease future occupational TMAH exposures.