Tetramethylenedisulfotetramine (TETS) is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...

used as a

rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despi ...

(rat poison). It is an odorless, tasteless white powder that is slightly soluble in water,

DMSO Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds ...

and

acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscibl ...

, and insoluble in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...

and

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

. It is a

sulfamide Sulfamide (IUPAC name: sulfuric diamide) is an organosulfur compound with the chemical formula and structure . Sulfamide is produced by the reaction of sulfuryl chloride with ammonia. Sulfamide was first prepared in 1838 by the French chemist H ...

derivative. It can be synthesized by reacting sulfamide with

formaldehyde Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...

under acidic condition. When crystallized from acetone, it forms cubic crystals with a melting point of 255–260 °C.

Toxicity and mechanism

TETS is a

neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature nerv ...

and

convulsant A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent exc ...

, causing lethal

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

s. Its effect is similar to but stronger than

picrotoxin Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Gree ...

, a GABA-A receptor antagonist widely used in research. As one of the most hazardous pesticides, it is 100 times more toxic than

potassium cyanide Potassium cyanide is a compound with the formula KCN. This colorless crystalline salt, similar in appearance to sugar, is highly soluble in water. Most KCN is used in gold mining, organic synthesis, and electroplating. Smaller applications inc ...

. TETS binds to neuronal GABA gated

chloride channels Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Several ...

, often causing

status epilepticus Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...

. No antidote is known. The lethal dose for humans is 7–10 mg. Poisoning is diagnosed by GC-MS and the treatment is mainly supportive, with large IV doses of a

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

(e.g

clonazepam Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class ...

) and

pyridoxine Pyridoxine, is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metabolic disor ...

to control symptoms. TETS is sequestered in tissues of poisoned

birds Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

and can thus pose severe risk of

secondary poisoning Secondary poisoning, or relay toxicity, is the poisoning that results when one organism comes into contact with or ingests another organism that has poison in its system. It typically occurs when a predator eats an animal, such as a mouse, rat, o ...

History

Previous research has documented the effectiveness of Tetramethylenedisulfotetramine against mice. The dangers of this chemical were first suspected in 1949. The U.S. Forest Service, looking to protect tree seeds for reforestation, noted its lethal effect against the rodent populations. Rather than repel wandering scavengers, the chemical was proved to be toxic to the local rodent population for up to 4 years. Continued experiments conducted by the U.S. Forest Service found no direct effect between TETS and the gastro-intestinal or renal systems of spinal dogs. In this same study, no effects were seen within the peripheral or skeletal nerve system, limiting symptoms of toxicity to the brain stem. Curtis and Johnson were the first to hypothesize TETS antagonistic behavior on GABA. An in-vitro study using superior cervical ganglion neurons of rats found TETS to antagonize the depolarization actions of GABA, while having no influence on the cholinomimetic agent carbachol. This evidence suggests that TETS may act as a non-competitive inhibitor for GABA. Further research findings using crustacean models, indicated a dose-dependent, non-competitive response to TETS that is reversible.

Research

In vitro and rapid screening tools

Recent studies have indicated the usefulness of pH sensitivity in identifying Chloride ion influx, resulting from GABAA receptor excitation. Other potential screening tools include spontaneous Calcium ion oscillations seen in hippocampal cell cultures from new born mice. This phenomenon can be measured by Calcium ion sensitive fluorescent dye. Further analyses showed that these Calcium ion oscillations are sensitive to MK-801 (an NMDA open channel blocker), suggesting that

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

operated channels are involved in TMDT induced spontaneous activity. When considering GABAA receptor activity, diazepam and pregnanolone reversed TMDT activity when applied to cell cultures individually and in combination.

MK-801 Dizocilpine ( INN), also known as MK-801, is a pore blocker of the ''N''-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is ...

and

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppress ...

show more antagonistic effects on TMDT than diazepam within cerebral cortical cell cultures of embryonic rats.

In vivo mouse models

Low dosages of ketamine and MK-801, administered separately, were associated with increased clonic seizures with no effect on tonic clonic seizures on mice exposed to TETS. Further analysis on the same sample of mice, found that dual administration of diazepine and MK-801 had a synergistic protective effect against tonic-clonic seizures and 24-hour lethality, as opposed to clonic seizures that were poorly controlled. Sequential administration diazepine and MK-801 for clonic control of seizures in TETS exposed mice, may indicate the benefits of benzodiazepine-NMDA receptor antagonist regimens used to treat TETS exposed patients.

Continued use in China

Its use worldwide has been banned since 1984, but due to continuing demand and its ease of production, it is still readily, although illegally, available in China and can be found in some illegally imported rat poisons. The best known Chinese rodenticide, containing about 6–20% TETS, is Dushuqiang, "very strong rat poison". It has been used for mass poisonings in China: in April 2004, there were 74 casualties after eating scallion-flavored pancakes tainted by their vendor's competitor; and in September 2002, 400 people were poisoned and 38 died from contaminated food. In 2002, there was one documented case of accidental poisoning in the US.

References

{{Convulsants Rodenticides GABAA receptor negative allosteric modulators Nitrogen heterocycles Convulsants Sulfur heterocycles Mass poisoning Neurotoxins Adamantane-like molecules Sulfamides Chloride channel blockers Sulfur–nitrogen compounds