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Toxicology Rounds: The Mysteries of Novichok and Brodifacoum

Gussow, Leon, MD

doi: 10.1097/01.EEM.0000535030.80353.31
Toxicology Rounds

Dr. Gussow is a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog at www.thepoisonreview.com, follow him on Twitter @poisonreview, and read his past columns at http://bit.ly/EMN-ToxRounds.

Figure

Figure

Former Russian spy Sergei Skripal and his daughter Yulia were attacked in Salisbury, England, in March with a little-known nerve agent that British scientists have identified as Novichok. Authorities there claimed that the assassination attempt could have only originated at the highest level of the Russian government. Russia denies any involvement.

Meanwhile, U.S. officials have documented a large cluster of cases of patients presenting with severe bleeding after smoking synthetic cannabinoid. The Illinois Department of Public Health reported 122 cases by April 12, including three fatalities. Laboratory tests identified the superwarfarin rat poison brodifacoum in biological specimens and product samples. It is not clear yet how brodifacoum got into these products.

These toxicology stories are still developing as I write this in April, and it is too early to provide a complete account, but we do know a few key things.

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Five Things about Novichok

  1. Novichok, Russian for “newcomer,” is an anticholinesterase nerve agent developed in the 1970s as part of a top-secret program in the Soviet Union designed to create powerful new chemical weapons that were not forbidden or detectable under existing agreements. Novichok is said to be 10 times as lethal as the nerve agent VX, which was used to assassinate Kim Jong-nam, the half-brother of North Korean leader Kim Jong-un. (“Five Things to Know about the Nerve Agent VX,” EMN 2017;39[5]:22; http://bit.ly/2HtKOpD.)
  2. No single chemical warfare agent is actually named Novichok. The term refers to a group of chemicals, including A-232, A-230, and A-234, and Substance 33.
  3. Novichok agents are produced by mixing common legal chemicals. The group seems to consist of binary agents, and, as Greaves and Hunt noted in their text, Responding to Terrorism: A Medical Handbook, “Novichok agents may consist of two separate ‘non-toxic’ components that, when mixed, become the active nerve agent.” This makes the agent safer to transport and more difficult to detect and solves its instability problem because the agents are produced just before deployment. (Philadelphia: Churchill Livingstone/Elsevier, 2011.)
  4. Novichok may have already been used as a murder weapon. Vladimir Uglev, a senior engineer in the Soviet chemical weapons program, claimed that one of the Novichok agents he helped develop was used in 1995 to assassinate Russian banker Ivan Kivelidi and his secretary. (Daily Mirror. March 24, 2018; http://bit.ly/2Hs5UVl.)
  5. We know very little about the Novichok agents. A PubMed search returns exactly one publication, in Russian. (Mikrobiologiia 2003;72[4]:563.) Searches for A-230 and Substance 33 are similarly unrevealing.
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Five Things about Brodifacoum

  1. Synthetic cannabinoids are sold as plant material that has been sprayed with an active chemical or as a vaping liquid. Patients who presented with bleeding after using synthetic cannabinoids said they smoked the product, according to the Illinois Department of Public Health. This suggests that brodifacoum is not deactivated by heat and is heat-stable.
  2. The New York Post article about these cases, “Synthetic Pot is Causing People to Bleed from Their Eyes and Ears,” did not reflect a typical presentation. (April 2, 2018; https://nyp.st/2HuenHC.) The Illinois DPH said patients developed severe bleeding, most commonly blood in the urine or bleeding from the gums or mouth in every case. Some patients developed flank or abdominal pain from internal bleeding; others presented with hemoptysis, epistaxis, and heavy menstrual flow.
  3. These cases of severe bleeding were not associated with just one synthetic cannabinoid product. The Illinois DPH and the Centers for Disease Control and Prevention determined that products laced with brodifacoum appeared under different names such as Bling Bling Monkey, Blue (and Red and Green) Giant, Matrix, and Scooby Snax. Most cases presented clinically in Illinois, but cases were also reported in Indiana, Missouri, Wisconsin, and Maryland.
  4. Coagulopathy from inhaling brodifacoum has been reported. One case report described a 21-year-old man who snorted a large volume of brodifacoum. (Lab Med2016;47[1]:63.) He presented with a mediastinal hemorrhage, bloody left pleural effusion, and an elevated INR at 12.9 (reference range is 0.8 to 1.1). He was treated with free frozen plasma, IV and PO vitamin K1, and a chest tube. Laboratory tests confirmed the brodifacoum. The patient was in the ICU for 22 days. The authors hypothesized that inhalation of brodifacoum avoided first-pass metabolism, accelerating and exacerbating the resultant bleeding.
  5. Brodifacoum intoxication from marijuana smoking has also been reported. A 17-year-old boy developed coagulopathy lasting more than a year after smoking marijuana mixed with brodifacoum. (Arch Pathol Lab Med 1997;121[1]:67.) It was not clear if brodifacoum altered the effects or kinetics of the cannabinoids.

Next month: The pharmacology, toxicology, and treatment of superwarfarins like brodifacoum.

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