Nerve agents are among the most potent and widely recognized chemical weapons. Recently, a new class of nerve agents, known as Novichok, has emerged as both a hazardous and frequently utilized tool in terrorist attacks. Medical professionals must gain a comprehensive understanding of the fundamental chemical and pharmacological properties of Novichok agents. This article provides a detailed review of the history, development, chemical structure, mechanism of action, toxicokinetics, and toxicology of these agents. Additionally, it discusses the latest diagnostic and treatment approaches for poisoning caused by Novichok agents. Contrary to earlier beliefs, Novichok poisoning shares similarities with other organophosphate toxins and can be effectively managed with timely and appropriate treatment. Given the global threat posed by terrorist incidents involving these agents, medical teams need to be well-versed in their characteristics to ensure optimal diagnosis and care for affected individuals.
Chemical weapons, or chemical warfare agents, are substances intentionally designed to inflict harm, disability, or death through their toxic characteristics [1-3]. These weapons are categorized alongside biological, radiological, and nuclear weapons as weapons of mass destruction (WMDs) because of their potential to cause large-scale casualties and destruction [1, 4, 5]. Chemical weapons can be classified based on factors such as chemical composition, physical state, toxicity level, harmful effects, and the specific organs they target. The main categories include nerve agents, blistering agents (vesicants), chemical asphyxiants, pulmonary irritants, tear agents (riot control agents), and incapacitating agents [6, 7].
Nerve agents are among the most dangerous and potent types of chemical weapons. These compounds, which fall under the organophosphate group, are among the most toxic due to their ability to inhibit the enzyme acetylcholinesterase. Historically, nerve agents like Tabun and Sarin have been used in warfare, including the Iran-Iraq War (1980-1988), and other agents such as Sarin and VX have been deployed in terrorist attacks. Recently, a new class of highly toxic nerve agents known as Novichok has emerged and has been used in recent terrorist incidents [2-9]. For medical professionals, especially those specializing in emergency care, clinical toxicology, forensic medicine, and forensic toxicology, understanding the chemical and toxicological properties of these agents is vital. This knowledge is essential for effectively responding to chemical terrorism, diagnosing and treating poisoned individuals, and investigating deaths resulting from chemical attacks [7-11].
This paper reviews the toxicological aspects of Novichok, covering its history, chemical structure, physicochemical properties, mechanism of action, toxicokinetics, clinical manifestations, diagnostic approaches, and the latest treatment options for poisoning.
In 1934, before the outbreak of World War II, Germany initiated a project at the Farben Chemical Industries Company, led by Dr. Gerhard Schrader, to develop new insecticides [12-15]. By 1936, Schrader’s team began focusing on organophosphorus-based compounds, eventually synthesizing over 2,000 chemicals within a decade [15, 16]. In 1936, the team succeeded in producing Tabun (GA), the first highly toxic organophosphate compound. In 1939, they developed Sarin (GB), which was found to be ten times more toxic than Tabun.
Until the early 1950s, most chemical weapons were designed as unitary weapons, meaning that ammunition such as bombs, bullets, mortars, grenades, and cannons were directly filled with toxic chemical agents and stored in this form until deployment. The risks associated with potential poisoning during the production, storage, and disposal of outdated or defective munitions, combined with the need for complex and expensive methods of destruction, led to environmental concerns regarding the storage of these weapons. These factors spurred research into reducing the risks associated with chemical weapons, which culminated in the development of the Binary Lethal Weapons System in the United States [17, 18].
The term “Novichok” is derived from the Russian word for “newcomer” [15-20]. It does not refer to a single substance but to a series of two-component chemical agents, which are analogs of Class A nerve agents. These substances include A-242 (Novichok-5), A-262 (Novichok-7), and others such as A-234 and Substance-33, all of which belong to the newer generation of nerve agents. Novichok is regarded as the third generation of nerve agents and the fourth generation of chemical weapons, with the first generation being sulfur mustard [15-18]. Information regarding the nature, physicochemical properties, and toxicology of Novichok agents was classified under the Foliant project. It remained restricted until the early 1990s, after which it was disclosed following the signing of the International Convention on the Prohibition of Chemical Weapons. In 1992, following the collapse of the Soviet Union, Will Mirzayanov, an expert in analytical chemistry and a former member of the Soviet State Institute of Organic Chemistry and Technology, published an article in Moscow News revealing details about this secret research project [15, 18, 21]. Following this revelation, Mirzayanov was arrested for treason but was later released due to public pressure, eventually emigrating to the United States. This disclosure alerted the Western world to the existence of a new generation of nerve agents more toxic than those previously known. However, much of the detailed information regarding the synthesis, toxicity, and military applications of Novichok remains unknown due to the highly classified nature of the project. Most of the available data comes from publications by researchers such as Vladimir O. Mirzayanov, Golf, and Andrey Zheleznyakov, who were involved in the project [18, 21]. Notably, until 2018, there were no published studies on Novichok in the reliable PubMed database, and only after the use of these agents in terrorist incidents in 2018 did references to them begin to appear. As of the time of this review, only 22 articles discussing the chemical and toxicological properties of Novichok agents have been published in journals indexed in this database.
Although Novichok agents have not been deployed as chemical weapons in conventional warfare, recent chemical terrorist attacks involving these nerve agents have drawn significant international attention. One of the earliest suspected uses of Novichok for chemical assassination was in 1995 in Moscow, where Russian banker Ivan Kiolidi and his secretary, Zara Ismailova, were reportedly poisoned through a contaminated office phone. Kiolidi, 46 years old, survived for three days, while Ismailova, 35, died in the hospital one month later, both having been exposed to a military-grade organophosphorus nerve agent. However, the world’s attention to Novichok agents intensified following the 2018 poisoning of former Russian spy Sergei Skripal and his daughter Yulia in the UK, which further highlighted the potential for these nerve agents to be used in high-profile chemical terrorism [18-22].
Novichok agents, like other organophosphates, irreversibly inhibit acetylcholinesterase, leading to a range of symptoms due to acetylcholine accumulation. The clinical signs of poisoning are similar to those caused by other nerve agents, with the severity depending on factors such as the type of agent, dosage, and the route of exposure. Symptoms may begin as soon as 30 seconds to 2 minutes after exposure. Poisoning typically results in a cholinergic toxic syndrome [1-3, 14, 23-25].
When exposed to small amounts, particularly through inhalation, the symptoms primarily affect the respiratory system. These may include a runny nose, difficulty breathing, chest tightness, bronchial constriction, and excessive mucus production in the airways, leading to coughing and wheezing. The duration of these symptoms can vary, lasting from several hours to days, depending on the severity of exposure [14, 26-30]. Miosis, or constricted pupils, is one of the first signs of either local (from liquid or vapor exposure) or systemic poisoning. Additionally, individuals may experience eye pain due to intense contraction of the ciliary muscles. This discomfort worsens with near-focus tasks or in bright light. Other ocular effects may include tearing, blurred vision, light sensitivity, eye spasms, and conjunctival redness.
If the poison is ingested, gastrointestinal symptoms such as nausea, vomiting, stomach cramps, diarrhea, and incontinence can occur [14, 31-35]. The progression of symptoms depends on how the agent enters the body: respiratory symptoms typically emerge first after inhalation, while gastrointestinal symptoms are more immediate after ingestion. The overall poisoning affects various body systems, including muscarinic, nicotinic, and central nervous system functions [14, 36-43].
In severe poisoning, the toxic effects of acetylcholine on nicotinic receptors in the neck ganglia lead to mydriasis (dilated pupils), tachycardia, and increased blood pressure. Additionally, muscle weakness that worsens with activity, twitching, muscle spasms, cramps, and flaccid paralysis can occur. Vasoconstriction, resulting in pale skin, is another symptom linked to nicotine poisoning caused by these agents. The weakening of respiratory muscles can lead to respiratory failure and, if untreated, death [43, 44].
In the central nervous system, even mild doses can cause symptoms such as anxiety, restlessness, mood swings, insomnia, vivid dreams, and nightmares. More severe effects include headaches, tremors, drowsiness, confusion, impaired judgment, memory loss, lack of coordination, and slower reactions. Seizures, absent reflexes, and abnormal breathing patterns, such as Cheyne-Stokes respiration, may develop. In the most severe cases, respiratory arrest can occur due to paralysis of the diaphragm and depression of the respiratory centers in the brainstem, leading to anoxia. Additionally, bradycardia and hypotension can result from the weakening of circulatory centers in the brain [1, 14, 43, 44].
The long-term effects of acute Novichok poisoning have been mostly observed in limited cases. One of the first known incidents of acute poisoning involved Andrei Zheleznyakov, a Russian scientist involved in the Novichok project, in 1987. He was exposed to Novichok aerosols due to a malfunction in the laboratory’s chemical hood. He quickly developed mydriasis, shortness of breath, excessive salivation, convulsions, bradycardia, respiratory paralysis, and coma. Although he survived after treatment, he suffered from severe neurological complications, including movement disorders and memory loss. He died five years later from liver cirrhosis, epilepsy, and inflammation of the trigeminal nerves [18]. Other cases of Novichok poisoning have shown a wide array of neurological and psychological complications, with delayed neurotoxicity appearing 1–3 weeks after exposure. These include severe muscle weakness, mental dysfunction, and memory issues [21, 43].
The treatment for acute Novichok poisoning follows the same general principles as for other organophosphorus poisoning, including immediate emergency care such as airway management, respiratory support, and circulatory stabilization. Decontamination, patient stabilization, and administration of antidotes are essential components of treatment. In critically ill patients, intubation and mechanical ventilation are necessary, alongside cardiovascular support and continuous monitoring [14, 43, 44].
While laboratory diagnosis is not essential for immediate treatment, it can provide valuable confirmation of poisoning, particularly in environmental samples (such as air, water, or soil) or biological samples from the affected individual or the deceased. Laboratory tests help distinguish poisoning from other conditions and determine the cause of death. However, due to the complexity, high cost, and specialized equipment requirements, the precise identification of the nerve agent involved may not always be feasible in standard laboratories.
One common diagnostic approach involves colorimetric tests to measure the activity of acetylcholinesterase and butyrylcholinesterase enzymes. This method is beneficial in hospitals for detecting exposure to organophosphorus agents, as these agents inhibit these enzymes. In practice, a blood sample from the patient is analyzed to determine acetylcholinesterase levels in red blood cells or butyrylcholinesterase levels in plasma. The Ellman method is frequently employed for this purpose, and the degree of enzyme inhibition correlates with the severity of poisoning. However, it is essential to note that this technique does not identify the specific agent involved [40, 45]. Additional diagnostic methods may include assessing enzyme activity, such as beta-glucuronidase and paraoxonase, which can help detect organophosphate poisoning [40].
For detecting nerve agents such as Novichok, Sarin, and VX in environmental samples, detection tubes are widely used. These devices rely on enzymatic color reactions and contain pellets coated with acetylcholinesterase or butyrylcholinesterase, along with a substrate and reagent. Detection tubes are portable, sensitive, easy to use, and effective across a range of environmental conditions, including those found in conflict zones or during terrorist attacks. They are an essential tool for field identification of nerve agents [45-48].
Butyrylcholinesterase enzyme is predominantly utilized in detection devices for nerve agents. The stability of the results depends heavily on the enzyme’s immobilization on a carrier, which has been optimized using materials such as magnesium aluminometasilicate. This material has a high contact surface area and serves as an effective protective layer for preparing detection pellets [49]. For identifying nerve agents, including Novichoks, especially in trace amounts within biological samples (such as blood, urine, and tissues like liver or lung) and non-biological samples (such as water, soil, air, food, or clothing), gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS-MS) methods are the most sensitive and reliable techniques [50].
Novichoks represent the fourth generation of chemical weapons and are classified as nerve agents in Category A. These agents, like other nerve agents, are organophosphorus compounds and act as non-competitive, irreversible inhibitors of acetylcholinesterase. Despite their similarities to earlier G and V-class nerve agents, their unique structural features suggest they may be more toxic than older nerve agents. Observations of their toxic clinical effects in chemical terrorism incidents, coupled with molecular simulations, provide new insights into their potency. However, the initial belief that Novichoks are more toxic than other nerve agents, such as VX, has been questioned. In fact, despite their significant toxicity, rapid and standard treatment, including symptomatic and supportive care, mechanical ventilation, and administration of antidotes like atropine, oximes, and benzodiazepines, can lead to successful management of poisoning cases. Given the increasing threat of these agents in chemical terrorism, it is crucial for medical personnel to be well-versed in the fundamental and clinical toxicology of Novichoks.
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