3-Quinuclidinyl benzilate

Physicochemical characteristics

BZ is a white crystalline powder with a bitter taste. It is odorless and nonirritating with delayed symptoms several hours after contact.

Structurally, BZ is an ester of benzilic acid joined to a quinuclidine unit and a hydroxy group.

Effects

Symptoms

Symptoms begin between 30 minutes and several hours of exposure. As a powerful anticholinergic agent, BZ produces a syndrome known as anticholinergic toxidrome: these include a range of psychological and physiological effects, with the most incapacitating effect being a state of delirium characterized by cognitive dysfunction, hallucinations, anxiolysis, and inability to perform basic tasks. The usual syndrome of physical anticholinergic effects are also present, including strong dilation of the pupils (potentially to the point of temporary blindness), fast heart rate, widening of blood vessels, dry mouth, and elevated body temperature. The readily-observable symptoms of the anticholinergic toxidrome are famously characterized by the mnemonic "Mad as a hatter, red as a beet, dry as a bone and blind as a bat" (and variations thereof). The effects generally last about three days, though some symptoms may persist up to six weeks.

Mechanism of action

BZ is an muscarinic antagonist, meaning it blocks muscarinic acetylcholine receptors, which the brain relies on for memory formation, attention and muscle movement.

Toxicity

Based on data from more than 500 reported cases of accidental atropine overdose and deliberate poisoning, the median lethal oral dose is estimated to be approximately 450 mg (with a shallow probit slope of 1.8). Some estimates of lethality with BZ have been grossly erroneous, and ultimately the safety margin for BZ is inconclusive due to lack of human data at higher dosage ranges, though some researchers have estimated it to be 0.5 to 3.0 mg/kg and an LD01 is 0.2 to 1.4 mg/kg (Rosenblatt, Dacre, Shiotsuka, & Rowlett, 1977).

Treatment

Antidotes for BZ include 7-MEOTA, which can be administered in tablet or injection form. Atropine and tacrine (THA) have also been used as treatments, THA having been shown to reduce the effects of BZ within minutes. Some military references suggest the use of physostigmine to temporarily increase synaptic acetylcholine concentrations.

History

Invention and research

BZ was invented by the Swiss pharmaceutical company Hoffman-LaRoche in 1951. By 1959, the United States Army showed significant interest in deploying it as a chemical warfare agent. As described in retired Army psychiatrist James Ketchum's autobiographical book Chemical Warfare: Secrets Almost Forgotten (2006), work proceeded in 1964 when a general envisioned a scheme to incapacitate an entire trawler with aerosolized BZ; this effort was dubbed Project DORK. BZ was ultimately weaponized for delivery in the M44 generator cluster and the M43 cluster bomb, until all such stocks were destroyed in 1989 as part of a general downsizing of the US chemical warfare program.

In 2022 a documentary film,* Dr Delirium and The Edgewood Experiments*, was broadcast on Discovery+, featuring an interview with Ketchum not previously shown.

Use and alleged use

Survivors of the 11-12 July 1995 Srebrenica massacre near Tuzla during the Bosnian War claimed they were attacked with a chemical agent that caused hallucinations, disorientation and strange behaviour.

In February 1998, the British Ministry of Defence accused Iraq of having stockpiled large amounts of a glycolate anticholinergic incapacitating agent known as ‘Agent 15’. Agent 15 is an alleged Iraqi incapacitating agent that is likely to be chemically identical to BZ or closely related to it. Agent 15 was reportedly stockpiled in large quantities prior to and during the Persian Gulf War. However, after the war the CIA concluded that Iraq had not stockpiled or weaponized Agent 15.

According to Konstantin Anokhin, professor at the Institute of Normal Physiology in Moscow, BZ was the chemical agent used to incapacitate terrorists during the 2002 Nord-Ost siege, resulting in at least 115 hostages perishing due to overdose. However, 2012 study concluded that a mixture of carfentanil and remifentanil was used instead.

In January 2013, an unidentified U.S. administration official, referring to an undisclosed U.S. State Department cable, claimed that "Syrian contacts made a compelling case that Agent 15, a hallucinogenic chemical similar to BZ, was used in Homs". However, in response to these reports a U.S. National Security Council spokesman stated,

Legality

BZ is listed as a Schedule 2 compound by the Organisation for the Prohibition of Chemical Weapons. It sees occasional use in biomedical research, for example to induce Alzheimer's-like symptoms in mice.

Footnotes

References

References

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4. Khatchadourian, Raffi. (2012-12-09). "Operation Delirium". The New Yorker.
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7. US Army FM 3-9
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13. Goodman, Ephraim. (2010). "Historical contributions to the human toxicology of atropine: behavioral effects of high doses of atropine and military uses of atropine to produce intoxication". Eximdyne.
14. The company was investigating anti-spasmodic agents, similar to [[tropine]], for treating [[Gastrointestinal disease
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30. Dlabkova, Alzbeta. (September 2021). "3‐Quinuclidinyl benzilate (agent BZ) toxicokinetics in rats". Basic & Clinical Pharmacology & Toxicology.