Quantitative analysis and stability of the rodenticide TETS (tetramine) in finished tap water

Knaack, Jennifer S.; Hamelin, Elizabeth I.; Magnuson, Matthew L.; Silvestri, Erin; Ash, Doris H.; Johnson, Rudolph C.

doi:10.1039/c3ay41912f

Cited by 3 publications

(7 citation statements)

References 20 publications

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“…The rodenticide TETS, in contrast, constitutes a chemical agent of serious concern. As previously reported (Knaack et al 2014), it is stable in drinking water for months. We now demonstrate here that TETS is not subject to metabolism by liver microsomes and that it persists in the body following acute intoxication.…”

Section: Discussionsupporting

confidence: 78%

“…1b). At physiological pH roughly 70% of picrotoxinin degrades within one hour at both room temperature and 37 °C, while it is more stable at an acidic pH of 4.0, where 75% remain intact after 24 h. TETS, in contrast, was stable at acidic, neutral and alkaline pH (not shown), thus confirming its previously published long-term stability in drinking water (Knaack et al 2014).…”

Section: Picrotoxinin Is Unstable In Aqueous Solutionssupporting

confidence: 86%

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Comparison of the toxicokinetics of the convulsants picrotoxinin and tetramethylenedisulfotetramine (TETS) in mice

et al. 2020

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Acute intoxication with picrotoxin or the rodenticide tetramethylenedisulfotetramine (TETS) can cause seizures that rapidly progress to status epilepticus and death. Both compounds inhibit γ-aminobutyric acid type-A (GABA A) receptors with similar potency. However, TETS is approximately 100 × more lethal than picrotoxin. Here, we directly compared the toxicokinetics of the two compounds following intraperitoneal administration in mice. Using LC/MS analysis we found that picrotoxinin, the active component of picrotoxin, hydrolyses quickly into picrotoxic acid, has a short in vivo half-life, and is moderately brain penetrant (brain/plasma ratio 0.3). TETS, in contrast, is not metabolized by liver microsomes and persists in the body following intoxication. Using both GC/MS and a TETS-selective immunoassay we found that mice administered TETS at the LD 50 of 0.2 mg/kg in the presence of rescue medications exhibited serum levels that remained constant around 1.6 μM for 48 h before falling slowly over the next 10 days. TETS showed a similar persistence in tissues. Whole-cell patch-clamp demonstrated that brain and serum extracts prepared from mice at 2 and 14 days after TETS administration significantly blocked heterologously expressed α 2 β 3 γ 2 GABA A-receptors confirming that TETS remains pharmacodynamically active in vivo. This observed persistence may contribute to the long-lasting and recurrent seizures observed following human exposures. We suggest that countermeasures to neutralize TETS or accelerate its elimination should be explored for this highly dangerous threat agent.

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Section: Discussionsupporting

confidence: 78%

Section: Picrotoxinin Is Unstable In Aqueous Solutionssupporting

confidence: 86%

Comparison of the toxicokinetics of the convulsants picrotoxinin and tetramethylenedisulfotetramine (TETS) in mice

et al. 2020

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“…Consistent correlation with theoretical values and ELISA results was observed. However, despite addition of isotope labeled 13 C-TETS as an internal standard and cleanup with solid-phase microextraction (SPME), GC/MS data were variable and generally provided overestimated results showing a strong effect of the matrix on the instrumental analysis (Table 2, part 1). Recoveries from serum samples were particularly affected by the matrix.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Currently, gas chromatography (GC) with different detection systems (MS, 9−13 MS/MS, 9,11 detection, 14 flame thermionic detection 15 ) is the main analytical technique used for TETS detection and quantification. This is due in part to poor ionization on LC-MS. Quantification protocols with good sensitivity were developed for tetramine detection in blood (8−500 ng/mL and LOD of 1 ng/mL), 14 urine (LOD around 3 ng/mL), 9,10,15 food (down to 0.2 ng/ g), 12 and beverages (0.5−100 ng/mL) 11,13 On the basis of clinical reports, depending on the severity of poisoning, the concentration of tetramine in the blood of victims varies widely from low ng/mL up to μg/mL. 7,8,16 In urine, the concentration of TETS is typically similar or slightly higher than in blood.…”

mentioning

confidence: 99%

Sensitive Immunoassay for Detection and Quantification of the Neurotoxin, Tetramethylenedisulfotetramine

et al. 2017

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Tetramethylenedisulfotetramine (TETS, tetramine) is a formerly used and highly neurotoxic rodenticide. Its lethality, recent history of intentional use for mass poisoning and the absence of a known antidote raises public health concerns. Therefore, rapid, high throughput and sensitive methods for detection and quantification of TETS are critical. Instrumental analysis method such as GC/MS is sensitive but not rapid or high-throughput. Therefore, an immunoassay selective to TETS was developed. The assay shows an IC50 of 4.5±1.2 ng/mL, with a limit of detection of 0.2 ng/mL, comparable to GC/MS. Performance of the immunoassay was demonstrated by a recovery study using known concentrations of TETS spiked into buffer, human and mouse serum matrices giving recoveries in the range of 80-120%. The assay demonstrated good correlation in TETS recovery with established GC/MS analysis. The immunoassay was then used to quantify TETS concentration in the serum of mice exposed to 2× LD50 dose of TETS and to monitor kinetics of TETS clearance from blood over a short period of time. TETS concentration in the serum reached 150 ng/mL without significant change over 4h post treatment. Results obtained with the immunoassay had good correlation with GC/MS analysis. Overall this immunoassay is an important tool to rapidly detect and quantify levels of TETS from biological samples with high sensitivity. The assay can be adapted to multiple formats including field or hospital use.

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“…It is an equimolar mixture of two tricyclic sesquiterpenes: picrotin and the active component picrotoxinin (Slater and Wilson 1951 ). TETS has similar physicochemical properties, but is easy to synthesize, tasteless and odorless, and stable in drinking water for months (Knaack et al 2014 ). These characteristics make TETS a tangible threat.…”

Section: Introductionmentioning

confidence: 99%

GABAA receptor subtype selectivity of the proconvulsant rodenticide TETS

2017

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The rodenticide tetramethylenedisulfotetramine (TETS) is a potent convulsant (lethal dose in humans 7–10 mg) that is listed as a possible threat agent by the United States Department of Homeland Security. TETS has previously been studied in vivo for toxicity and in vitro in binding assays, with the latter demonstrating it to be a noncompetitive antagonist on GABAA receptors. To determine whether TETS exhibits subtype selectivity for a particular GABAA receptor combination, we used whole-cell patchclamp to determine the potency of TETS on the major synaptic and extrasynaptic GABAA receptors associated with convulsant activity. The active component of picrotoxin, picrotoxinin, was used as a control. While picrotoxinin did not differentiate well between 13 GABAA receptors, TETS exhibited the highest activity on α2β3γ2 (IC50 480 nM, 95% CI 320–640 nM) and α6β3γ2 (IC50 400 nM, 95% CI 290–510 nM). Introducing β1 or β2 subunits into these receptor combinations reduced or abolished TETS sensitivity, suggesting that TETS preferentially affects receptors with α2/β3 or α6/β3 composition. Since α2β3γ2 receptors make up 15–20% of the GABAA receptors in the mammalian CNS, we suggest that α2β3γ2 is probably the most important GABAA receptor for the seizure-inducing activity of TETS.

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Quantitative analysis and stability of the rodenticide TETS (tetramine) in finished tap water

Cited by 3 publications

References 20 publications

Comparison of the toxicokinetics of the convulsants picrotoxinin and tetramethylenedisulfotetramine (TETS) in mice

Comparison of the toxicokinetics of the convulsants picrotoxinin and tetramethylenedisulfotetramine (TETS) in mice

Sensitive Immunoassay for Detection and Quantification of the Neurotoxin, Tetramethylenedisulfotetramine

GABAA receptor subtype selectivity of the proconvulsant rodenticide TETS

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