2,6-Dithia-1,3,5,7-tetraazatricyclo3.3.1.13,7decane, 2,2,6,6-tetraoxide

Description

Tetramethylenedisulfotetramine (2,6-dithia-1,3,5,7-tetraazadamantane, 2,2,6,6-tetraoxide, TETS) is a highly toxic heteroadamantane rodenticide. It is an odorless, tasteless, white crystalline powder that is slightly soluble in water (0.25 mg ml^-1), dimethyl sulfoxide and acetone. It was originally synthesized in 1933 as a resinous condensation product of sulfamide and formaldehyde and used commercially in pillows and upholstery as an impregnating stiffening and antimold agent. However, in 1950, a massive poisoning of German workers in the furniture manufacturing industry was linked to ‘Crinex’ wool, which contained TETS as a byproduct of processing. Early experimental studies in rodents revealed that TETS was an extremely toxic convulsant agent. It was also discovered at this time that TETS is a highly effective rodent repellent, which resulted in its use during reforestation projects to prevent seed predation by rodents. However, because of its high toxicity in mammals, including humans, and its persistence in the environment, many countries banned its production and use in 1984. This ban became worldwide when China issued similar restrictions in 1991. However, due to its relative ease of synthesis and low cost, TETS remains available on the black market, particularly in many rural areas of China and in regions outside of China that have large Asian populations.

Uses

Despite the worldwide ban on its production and use, TETS continues to be used illicitly as a rodenticide in various regions of the world. In China, TETS is known as ‘Dushuqiang’, ‘Meishuming,’ or ‘Shanbudao.’ In 2000, the National Poison Control Center of China revealed that 74% of commercial rodenticides contained illegal chemicals, with TETS found in nearly 50% of these pesticides. From 1977 to 2002, it was estimated that there were thousands of cases of TETS poisoning in China, resulting in hundreds of deaths. A more recent analysis indicates that between 1991 and 2010, there were over 14 000 cases of TETS intoxication in China, of which 932 resulted in death. In 2003, the first case of TETS intoxication in the United States was reported: a healthy 15-month-old girl was poisoned following accidental ingestion of a rodenticide imported from China that contained TETS. While many cases are thought to be due to accidental poisonings, there have been numerous reports of TETS being used to intentionally poison humans.

Environmental Fate

Although TETS has a relatively low solubility in water (0.25 mg kg^-1), it is quite stable, thus making it relatively persistent in the environment. It is reported that TETS retains biological activity in water for 6 weeks to 5 months after preparation. It is believed that TETS bioaccumulates (despite a predicted octanol:water coefficient of 0.07) and that contact with poisoned animals can result in intoxication, as demonstrated by reports of dogs dying after eating TETS-poisoned rats and by Chinese newspapers warning against consuming meat from dogs that were suspected to have eaten TETS-poisoned rats.

Toxicity evaluation

TETS is a potent convulsant neurotoxicant. TETS has no major effects on peripheral neuromuscular or autonomic transmission and its toxicity appears to be due primarily to actions on the central nervous system. Postmortem studies of TETSpoisoned patients revealed significant pathology in the brain, including degeneration in the basal ganglia, subarachnoid hemorrhages, cerebral and cerebellar bleeding, and brainstem hemorrhages. In cases of extreme intoxication, edema, congestion, and hemorrhages are commonly found in not only the brain but also the heart, lungs, liver, and kidneys. Markers of severe tissue damage (aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, lactate dehydrogenase, a-hydroxybutyrate dehydrogenase, and creatine phosphokinase isoenzyme MB) are also higher in patients who succumbed to TETS poisoning compared to patients who survived. Additional consequences of TETS intoxication include low potassium levels (hypokalemia), low phosphorus levels (hypophosphatemia), abnormal sodium levels (hypo- or hypernatremia), metabolic acidosis, circulatory hypoxia, and renal tubular damage as demonstrated by elevated levels of Nacetyl- b-D-glucosaminidase and retinol-binding protein. Collectively, these findings are consistent with reports that death following acute TETS intoxication is primarily due to multiple organ dysfunction syndrome.
It is generally believed that the convulsant action of TETS is mediated by noncompetitive reversible antagonism of the GABAA receptor chloride channel. TETS blocks g-aminobutyric acid (GABA)-dependent chloride influx in diverse experimental preparations and inhibits the binding of [35S] TBPS to GABAA receptors. GABAA receptors are composed of different subunits (α1–α6, β1–β4, γ1–γ3, δ, ξ, π, and ρ1–ρ3), and require at least one α, β, and γ subunit to be fully functional. TETS is active on native GABAA receptors and recombinantα1β3γ2 receptors, but has no effect on recombinant receptors composed entirely of β3 subunits. Picrotoxin, which similarly induces convulsions via GABA receptor antagonism, is much more selective for the β3 receptor compared to native receptors and the recombinant α1β3γ2 hetero-oligomer.