Tetramethylenedisulfotetramine neurotoxicity: What have we learned in the past 70 years?

Tetramethylenedisulfotetramine (tetramine, TETS, TMDT) is a seizure-producing neurotoxic chemical formed by the condensation of sulfamide and formaldehyde. Serendipitously discovered through an occupational exposure in 1949, it was promoted as a rodenticide but later banned worldwide due to its danger to human health. However, exceptional activity of the agent against rodent pests resulted in its clandestine manufacture with large numbers of inadvertent, intentional, and mass poisonings, which continue to this day. Facile synthesis, extreme potency, persistence, lack of odor, color, and taste identify it as an effective food adulterant and potential chemical agent of terror. No known antidote or targeted treatment is currently available. In this review we examine the origins of tetramethylenedisulfotetramine, from its identification as a neurotoxicant 70 years ago, through early research, to the most recent findings including the risk it poses in the post-911 world. Included is the information known regarding its in vitro pharmacology as a GABAA receptor channel antagonist, the toxic syndrome it produces in vivo, and its effect upon vulnerable populations. We also summarize the available information about potential therapeutic countermeasures and treatment strategies as well as the contribution of clinical development of TMDT poisoning to our understanding of epileptogenesis. Finally we identify gaps in our knowledge and suggest potentially fruitful directions for continued research on this dangerous, yet intriguing compound.