Introduction

Overview

This article describes the neurologic effects of various chemical agents used for chemical warfare or terrorism. The pathogenesis and pathophysiology as well as clinical manifestations of the important agents are described. Management is focused on organophosphates as chemical agents, particularly sarin. Neurologic manifestations can be acute, and there are some late sequelae in survivors.

Historical note and terminology

The history of chemical weapons spans many centuries, but most important events occurred since World War I (14).

Early use of chemical weapons. Aboriginal peoples on several continents employed toxins for hunting and warfare (eg, curare and amphibian-derived toxins as arrow poisons by aboriginal South Americans; "upas" as an arrow poison by Malaysians) (19).

However, many of the claims concerning the use of chemical weapons in ancient history are not supported by rigorous evidence and, although seemingly referred to in the introductions to numerous articles, editorials, and monographs on chemical weapons and terrorism, are unreferenced and uncritical rehashings of speculative and dubious claims, are often reiterated and amplified on social media (29). For example, oft-repeated claims of Assyrians poisoning enemy water supplies with ergot are unsupported by any rigorous evidence, even though it is known that Assyrians knew of ergot.

Much more plausible are accounts of the use of noxious smoke to incapacitate or sometimes to directly kill opponents, as employed, for example, by the Spartans lighting a mixture of wood, pitch, and sulfur under the walls of a besieged Athenian city during the Peloponnesian War (431-404 BCE). Another example is the Sassanians (Neo-Persians) burning bitumen and sulfur crystals to give off dense clouds of choking sulfur dioxide gas during the Roman-Persian Wars (54 BCE to 628 CE).

Napoleonic Wars (1803-1815). Thomas Cochrane (1775-1860), 10th Earl of Dundonald, styled "Lord Cochrane," was a British naval flag officer of the Royal Navy, mercenary, and radical politician. He had such success as a captain during the Napoleonic Wars that Napoleon nicknamed him "le Loup des Mers"--"the Sea Wolf" (21). In 1812, Cochrane proposed a plan to use "stink vessels" (ie, sulfur vessels) against the French Navy (21; 104). These ships, layered with coke and sulfur, would be sent amongst the French fleet and ignited to emit a choking gas (ie, a combination of sulfur dioxide, hydrogen sulfide, and carbonyl sulfide). The British Navy decided not to pursue his "secret plan"; however, he did communicate his plan with Lyon Playfair, who presented a modified proposal for gas warfare at the time of the Crimean War.

Crimean War (1853-1856). In 1853, at the beginning of the Crimean War, British scientist and politician Lyon Playfair (1818-1898) was appointed Secretary of the Department of Science, in which capacity he advocated the use of poison gas against the Russians:

World War I. In the last century, poisonous warfare agents were used for the first time on the battlefields of Europe during World War I, which led to a rapid escalation in the development of gas masks (full face respirator masks) and even early full-body hazmat suits (also referred to as haz-suits or hazardous materials suits), which required training to be used in combat situations and were soon employed in combat by soldiers on both sides in the war.

In close combat in the presence of choking agents, one technique was to try to rip off the enemy soldier’s gas mask.

The use of chemical weapons also stimulated the development of simple but effective techniques to eliminate heavier-than-air toxic gases (eg, chlorine) from trenches, beating the gas from the trench by oscillating an Ayrton trench fan (a stiffened canvas blade on a stick). The fan was the idea of British engineer, mathematician, physicist, inventor, and suffragette Hertha Ayrton (born Phoebe Sarah Marks; 1854-1923).

From June 1917 to November 1918, the United States shipped nearly 4 million gas masks overseas along with nearly 2 million extra canisters, 350,000 horse gas masks, and approximately 28,000 trench fans (10).

In the setting of choking agents in World War I, an often-overlooked consideration was the need to protect both soldiers and horses.

World War I was a transition period between heavy reliance on horse-borne cavalry units and the later use of tanks. Horses were better than mechanized vehicles at traveling through deep mud and over rough terrain. Horses were used for reconnaissance, carrying messengers, hauling shells, and pulling artillery, ambulances, and supply wagons. France, not Germany, was the first to use a chemical weapon of sorts when they deployed tear gas in August 1914. The lachrymatory agent used was either xylyl bromide (smelling "pleasant and aromatic") or ethyl bromoacetate ("fruity and pungent"); both liquids must be atomized to be dispersed as weapons. These substances irritate the eyes, cause uncontrolled tearing, and, in large doses, can cause temporary blindness and breathing difficulties. Because symptoms usually resolve within 30 minutes, tear gas was never very effective as a weapon.

The use of lethal chemical weapons began on April 22, 1915, when at 5 pm, German specialist troops released asphyxiating chlorine gas from cylinders embedded in the ground. A yellow-green cloud of chlorine gas drifted downwind and smothered the Allied line on the northern end of the Ypres salient, causing agony, panic, and death. Chlorine reacts with moisture to form hypochlorous acid (HClO) and hydrochloric acid (HCl); when this reaction occurs in the respiratory passages, the effect is devastating, causing acute and persistent damage (113; 48).

Chlorine’s effectiveness as a weapon was short-lived, however, because its color and odor made it easy to recognize, allowing time to don a gas mask. Even soldiers without gas masks could mitigate the adverse effects by placing water- or urine-soaked rags over their mouths and noses (the chlorine reacted with the water in the rag rather than water coating the respiratory passageways). Additionally, releasing the gas in a cloud posed problems, as the British learned when they first attempted to use chlorine at Loos, France, on September 25, 1915: the wind shifted, carrying the gas back onto their own men.

During World War I, the United States manufactured chemical weapons at U.S. military plants in Edgewood, Maryland; Stanford, Connecticut; Hastings-on-Hudson, New York; Kingsport, Tennessee; Croyland, Pennsylvania; and Willoughby, Ohio (10). The manufactured weapons included: (1) blister agents (ie, mustard gas and lewisite) and the precursor chemical sulfur monochloride (ie, disulfur dichloride); (2) choking or pulmonary agents (ie, bromobenzylcyanide, chlorine, chloripicrin, and phosgene); and (3) a vomiting agent (ie, diphenylchloroarsine, believed to penetrate the gas masks of the time and to cause violent sneezing, forcing removal of the protecting device; the Germans called it Maskenbrecher [mask breaker]) (10). In addition, five commercial chemical plants manufactured phosgene and mustard gas as well as precursor chemical-weapon chemicals: Oldbury Electro-Chemical Company in Niagra Falls, New York; Dow Chemical Compan in Midland Michigan; Frank Hemingway Inc. in Bound Brook, New Jersey; Charleston Chemical Company in Charleston, West Virginia; and National Analine & Chemical Company in Buffalo, New York (10).

Treaty of Versailles (1919). In the Treaty of Versailles (1919) at the end of World War I, the victorious Allies reaffirmed a prohibition of the use of poisonous gases in warfare and forbade Germany to manufacture or import them. Similar provisions were included in the peace treaties with Austria, Bulgaria, and Hungary.

Geneva Protocol (1925). The 1925, Geneva Protocol prohibited the use of chemical and biological weapons in war. The Protocol was drafted and signed at a conference held in Geneva under the auspices of the League of Nations from May 4 to June 17, and it entered into force on February 8, 1928. It specifically precluded "the use in war of asphyxiating, poisonous, or other gases and of all analogous liquids, materials, or devices." Despite this hopeful development, countries continued to develop chemical warfare capabilities, and some countries considered chemical warfare a suitable means to achieve military goals.

Germany's development of nerve agents (1936-1949). Nerve agents were discovered inadvertently by German chemist Gerhard Schrader (1903-1990) at the IG Farben chemical conglomerate. Schrader had been charged with developing new insecticides to help reduce Germany’s reliance on food imported from abroad and had been successful in discovering several very effective insecticides, including "bladan" (the first fully synthetic contact insecticide, containing the organophosphate compound hexaethyl tetraphosphate), and parathion (E 605). After failing to make viable fluorine- and sulfur-based pesticides, Schrader began experimenting with molecules that combined phosphorus and cyanide. An early candidate was so poisonous that Schrader was hospitalized for several weeks after being exposed to trace amounts. On December 23, 1936, Schrader synthesized "preparation 9/91," later named tabun; dilute solutions destroyed insect food pests but also caused dyspnea, vomiting, diarrhea, mydriasis, sialorrhea, diaphoresis, and death in apes and other mammals.

Although this indiscriminate poison was clearly not a safe pesticide, IG Farben alerted the German military about this new poisonous compound. During World War II, teams led by Schrader discovered two more organophosphate nerve agents, and a fourth after the war, yielding the following: tabun (1936), sarin (1938), soman (1944), and cyclosarin (1949). Nazi Germany manufactured an extensive stockpile of military-grade nerve agents but never used them against the Allies. The Nazi nerve agent stockpiles were only discovered at the end of World War II.

World War II and the Holocaust. Unlike World War I, World War II did not see battlefield use of chemical weapons, even though that possibility was a worrying concern--so much so, in fact, that British Prime Minister Winston Churchill carried a gas mask with him.

During World War II, Nazi Germany and its collaborators conducted widescale poisoning and genocidal extermination of European Jews. Between 1941 and 1945, Nazi Germany and its collaborators systematically murdered some 6 million Jews across German-occupied Europe--around two thirds of Europe's Jewish population. The murders were carried out in mass shootings, by a policy of extermination through labor and starvation in concentration camps, and in gas chambers and gas vans in German extermination camps, especially in occupied Poland (ie, Auschwitz-Birkenau, Bełżec, Chełmno, Majdanek, Sobibór, and Treblinka). The gas chambers consisted of a sealed chamber into which a poisonous or asphyxiant gas was introduced, usually carbon monoxide or hydrogen cyanide (Zyklon B), both of which specifically inhibit cytochrome c oxidase of the human mitochondrial respiratory chain (03; 22). The gas vans or gas wagons (German: Gaswagen) were simply trucks re-equipped as mobile gas chambers. Nazi Germany developed and used gas vans on a large scale as an extermination method to murder inmates of asylums, Jews, Poles, Romani people, and prisoners in occupied Poland, Belarus, Yugoslavia, and the Soviet Union.

Zyklon B was the trade name of a cyanide-based pesticide invented in Germany in the early 1920s. Hydrogen cyanide was first used as a pesticide in California in the 1880s for fumigating citrus trees. Research by German chemist Fritz Haber (1868-1934) of the Kaiser Wilhelm Institute for Physical Chemistry and Electrochemistry led to the founding in 1919 of Deutsche Gesellschaft für Schädlingsbekämpfung mbH (Degesch), a state-controlled consortium formed to investigate military use of the chemical. Research at Degesch led to the development of Zyklon (ie, Cyclone in English, later known as Zyklon A), a pesticide that released hydrogen cyanide on exposure to water and heat. Degussa purchased Degesch in 1922; their chemists, including Walter Heerdt (1888-1958) and Bruno Tesch (1890-1946), devised a method of packaging hydrogen cyanide (prussic acid) in sealed canisters along with a cautionary eye irritant and an adsorbent (eg, diatomaceous earth). The new product, known as Zyklon B to distinguish it from the earlier version, was initially used for delousing clothing and fumigating ships, warehouses, and trains. The Nazis started using Zyklon B in extermination camps in early 1942 to murder prisoners during the Holocaust. Following the end of World War II, Tesch was arrested by the British as a war criminal, tried, and executed in 1946 for knowingly selling the product for use on humans.

After World War II. After World War II, new types of organophosphorus chemical warfare agents were developed, such as Novichoks in the Soviet Union/Russia.

Iraq's use of chemical weapons against Iran in the Iran-Iraq War (1980-1988). Iraq used the blister agent mustard gas from 1983 and the nerve gas Tabun from 1985 as it faced attacks from Iranian troops and poorly trained but loyal volunteers.

Halabja massacre (1988). The Halabja massacre was a massacre of Kurdish people in Halabja in northern Iraq on March 16, 1988, during the closing days of the Iran-Iraq War. Iraqi war planes and artillery pounded Halabja with mustard gas and the nerve agents sarin and tabun, apparently as punishment because some Kurdish guerrilla forces had joined the Iranian offensive (46). The incident was the largest chemical weapons attack directed against a civilian-populated area in history, killing between 3,200 and 5,000 people and injuring 7,000 to 10,000 more, most of them civilians.

Aum Shinrikyo chemical (and biological) terrorism. Between 1990 and 1995, the Aum Shinrikyo cult in Japan launched 17 known attacks with chemical and biological weapons, 10 with chemical weapons (four with sarin, four with VX, one with phosgene, and one with hydrogen cyanide) and seven with biological agents (four with anthrax and three with botulinum toxin, although these all failed because the microbial strains were nonvirulent). In addition, cult members killed 20 dissident members with VX. The cult has also been linked more tenuously to more than 19 other chemical and biological weapon attacks and attempted attacks (13 attacks where Aum involvement is suspected and six possible copycats).

Tokyo subway sarin attack (1995). On June 27, 1994, in a dry run for a subsequent and more massive act of domestic terrorism, the Aum Shinrikyo cult released sarin from a vehicle driving through the industrial and resort city of Matsumoto, Japan, killing seven people and injuring some 500 more.

The cult perpetrated a major act of domestic terrorism in Tokyo on March 20, 1995. In five coordinated attacks, the perpetrators released sarin on three lines of the Tokyo Metro (then the Teito Rapid Transit Authority) during rush hour. The perpetrators had boarded the subway trains with plastic bags containing sarin and released the gas by simply poking holes in the bags with the metal tips of umbrellas. Even though emergency personnel responded quickly to the scene, the attack killed 13 people and injured over 1,000, of whom 17 were critically injured (ie, requiring intensive care), 37 were moderately to severely injured (ie, with muscular twitching and gastrointestinal problems), and 984 were slightly injured (ie, with pinpoint pupils but no other symptoms).

When police later investigated documents seized in the cult office, they discovered the five-step process the cult used to manufacture sarin: (1) phosphorus trichloride was reacted with methanol to produce trimethyl phosphite; (2) trimethyl phosphite was converted to dimethyl methylphosphonate (DMMP) through a heat-induced rearrangement; (3) DMMP was reacted with phosphorus pentachloride by applying heat to produce methylphosphonyl dichloride; (4) methylphosphonyl dichloride was reacted with sodium fluoride to produce methylphosphonyl difluoride; and (5) methylphosphonyl difluoride and methylphosphonyl dichloride were mixed with isopropyl alcohol to produce sarin.

Tokyo subway attempted cyanide attacks (1995). On May 5, 1995, a burning paper bag was discovered in a toilet in Tokyo's Shinjuku subway station. On examination, it was found to be a hydrogen cyanide device; had it not been extinguished in time, it would have released enough gas into the ventilation system to potentially kill 10,000 commuters. Two months later, on July 4th, several undetonated cyanide devices were found at other locations in the Tokyo subway. Later, when police raided the facilities of the cult, stockpiles of chemicals were found that could be used for producing enough sarin to kill 4 million people.

Chemical Weapons Convention (1997). The Eighteen Nation Committee on Disarmament, sponsored by the United Nations in 1961, originally considered disarmament and nuclear test controls. Between 1965 and 1968, the committee negotiated the Treaty on the Non-Proliferation of Nuclear Weapons. By 1984, the Eighteen Nation Committee on Disarmament evolved into the Conference on Disarmament. On September 3, 1992, the Conference on Disarmament submitted to the United Nations General Assembly its annual report, which contained the text of the Chemical Weapons Convention (CWC)--officially the Convention on the Prohibition of the Development, Production, Stockpiling, and Use of Chemical Weapons and on their Destruction. The General Assembly approved the CWC on November 30, 1992, and the U.N. Secretary-General opened the CWC for signature in Paris on January 13, 1993. The CWC remained open for signature until it entered into force on April 29, 1997.

The CWC is an arms control treaty administered by the Organisation for the Prohibition of Chemical Weapons (OPCW, an intergovernmental organization based in The Hague, The Netherlands). The CWC prohibits the large-scale use, development, production, and stockpiling of chemical weapons and their precursors, except in small amounts for limited purposes (ie, research, medical, pharmaceutical, or protective). The CWC augments the Geneva Protocol of 1925, which banned the use but not the development or possession of chemical and biological weapons. The CWC also includes extensive verification measures, such as on-site inspections, unlike the 1975 Biological Weapons Convention, which lacked a verification process.

As of October 2022, 193 countries have become parties to the CWC and accept its obligations. Members must follow this prohibition and destroy all current chemical weapons under OPCW verification. The CWC has provisions for systematic evaluation of chemical production facilities and for investigations of allegations of chemical weapons use and production based on other parties' intelligence. Israel signed the CWC in 1993 but has not yet ratified the agreement, whereas three other United Nations member states (Egypt, North Korea, and South Sudan) have neither signed nor acceded to the treaty.

Under the CWC, as of October 2022, 99% of the world's declared chemical weapons stockpiles have been destroyed (https://www.opcw.org, Accessed October 21, 2022).

Syrian Civil War (2012-2018). Chemical weapons were used repeatedly in the Syrian Civil War beginning in 2012. Both the Syrian government of Bashar al-Assad and militants of the Islamic State of Iraq and the Levant (ISIL), an Islamist terrorist organization, used chemical weapons, with most attacks carried out by the Syrian government. Chlorine was the most used agent, and sarin and sulfur mustard were also used (99). Chlorine was used in 92% of confirmed chemical weapons attacks attributable to the Assad regime (which was responsible for 98% of all recorded attacks over the course of the war), including the fateful April 7, 2018 attack on Douma by the Syrian army, which killed between 40 and 50 people and injured over 100 (99). Almost half of the attacks between 2014 and 2018 were delivered by aircraft, and less than a quarter were delivered from the ground. The deadliest attacks were the August 2013 sarin attack in Ghouta (reportedly killing between 281 and 1,729 people) and the April 2017 sarin attack in Khan Shaykhun (killing at least 89 people).

Attacks in 2013 prompted international pressure, resulting in an agreement with the Syrian Armed Forces to the supervised destruction of their chemical weapons. However, despite the disarmament process, completed on June 23, 2014, dozens of incidents with suspected use of chemical weapons followed throughout Syria. In April 2018, following at least 18 visits to Syria for inspections, the technical secretariat of the OPCW was unable to "verify that Syria had submitted a declaration that could be considered accurate and complete" (95).

Continued threat of chemical weapons. Despite the CWC, there is still a real threat of chemical weapon use (61), particularly in acts of terrorism and assassination. Consequently, soldiers routinely receive training in warfare during a chemical attack, particularly in using protective equipment during training with lachrymatory agents, realistic combat simulations, and the management of chemical weapons casualties.

Assassination weapons and weapons of chemical terrorism. VX and Novichok agents have been used to carry out political assassinations by both states and transnational terrorist organizations, as in the case of Russian dissident and opposition leader Alexei Navalny, who was poisoned in August 2020, evacuated in a comatose condition to Germany, and successfully treated at the Charite Hospital in Berlin.

In 12 attempted assassinations from 1994 to 2020, there were 12 designated targets, but one involved three simultaneous targets, and at least two individuals were targeted twice (Table 1) (Taro Takimoto, Noboru Mizonu, and possibly Emilian Gebrev) (105). Only three of the attempts killed the intended targets, whereas an additional 10 people (ie, not targets) were killed. Therefore, nerve agents are a low-efficiency assassination weapon with a high likelihood of collateral damage. A single attempt on three simultaneous targets injured more than 500 people who were apparently not the primary intended target (although that event in Matsumoto Japan in 1994 may have had a secondary terroristic element).

Table 1. Nerve Agents Employed in Assassinations and Assassination Attempts

Chemical weapons of mass destruction. According to the U.S. Department of Homeland Security, "A weapon of mass destruction is a nuclear, radiological, chemical, biological, or other device that is intended to harm a large number of people" (Department of Homeland Security, Accessed October 16, 2022). This article addresses chemical agents used as weapons of mass destruction, as agents of chemical terrorism, and as assassination agents, providing a historical overview of chemical agents that have been developed or used in this capacity in the 20th century (Table 2) and then focuses on the class of chemical agents that selectively targets the nervous system: nerve agents.

Table 2. Agents Developed as Chemical Weapons in the 20th Century

Scope of this article. For this article, agents that were not intended to cause direct harm to people are not addressed; therefore, for example, agent orange is not considered here because it was intended as a defoliant to eliminate forest cover and crops for North Vietnamese and Viet Cong troops. In addition to Agent Orange’s active ingredients, Agent Orange contained significant amounts of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a type of dioxin; dioxin was not intentionally added to Agent Orange but was instead a byproduct produced during the manufacture of herbicides.

This article also does not address either the use of toxins (ie, an antigenic poison or venom of plant or animal origin, causing disease when present at low concentration in the body) or the use of nuclear or radiological agents.