Throughout history, mass poisonings have caused suffering and misfortune. From the ergot epidemics of the Middle Ages to contemporary industrial disasters, these mass events have had great political, economic, social, and environmental ramifications. Particularly within the past 100 years, as the number of toxins and potential toxins has risen dramatically, toxic disasters have become increasingly common events. The sites of some of these events—Bhopal (India), Chernobyl (Ukraine), Jonestown (Guyana), Love Canal (New York), Minamata Bay (Japan), Seveso (Italy), West Bengal (India)—have come to symbolize our increasing potential for environmental toxicity. Globalization has led to the proliferation and rapid distribution of toxic chemicals throughout the world. Many factories that store large amounts of potentially lethal chemicals are not secure. Given the increasing attention to terrorism preparedness, an appreciation of chemicals as agents of opportunity for terrorists has suddenly assumed great importance. This chapter provides an overview of some of the most consequential and historically important toxin-associated mass poisonings that represent human and environmental disasters.

Inhalation of toxic gases and oral ingestions resulting in food poisoning tend to subject the greatest number of people to adverse consequences of a toxic exposure. Toxic gas exposures may be the result of a natural disaster (volcanic eruption), industrial mishap (fire, chemical release), chemical warfare, or an intentional homicidal or genocidal endeavor (concentration camp gas chamber). Depending on the toxin, the clinical presentation may be acute, with a rapid onset of toxicity (cyanide), or subacute or chronic, with a gradual onset of toxicity (air pollution).

One of the earliest recorded toxic gas disasters resulted from the eruption of Mount Vesuvius near Pompeii, Italy, in 79 A.D. (Table 2–1). Poisonous gases generated from the volcanic activity reportedly killed thousands of people.³⁵ A more recent natural disaster occurred in 1986 in Cameroon, when excessive amounts of carbon dioxide spontaneously erupted from Lake Nyos, a volcanic crater lake.¹⁹ Approximately 1,700 human and countless animal fatalities resulted from exposure to this asphyxiant.

A toxic gas leak at the Union Carbide pesticide plant in Bhopal, India, in 1984 resulted in one of the greatest civilian toxic disasters in modern history.¹⁴⁴ An unintended exothermic reaction at this carbaryl-producing plant caused the release of more than 24,000 kg of methyl isocyanate. This gas was quickly dispersed through the air over the densely populated area surrounding the factory where many of the workers lived, resulting in at least 2,500 deaths and 200,000 injuries.⁸⁸ The initial response to this disaster was greatly limited by a lack of pertinent information about the toxicity of this chemical as well as the poverty of the residents. A follow-up study 10 years later showed persistence of small-airway obstructive disease among survivors as well as chronic ophthalmic problems.³¹ Calls for improvement in disaster preparedness and strengthened “right-to-know” laws regarding potential toxic exposures resulted from this tragedy.^50,144

The release into the atmosphere of 26 tons of hydrofluoric acid at a petrochemical plant in Texas in October 1987 resulted in 939 people seeking medical attention at nearby hospitals. Ninety-four people were hospitalized, but there were no deaths.¹⁵⁴

More than any other single toxin, carbon monoxide is involved in the largest number of toxic disasters. Catastrophic fires, such as the Cocoanut Grove Nightclub fire in 1943, have caused hundreds of deaths at a time, many of them from carbon monoxide poisoning.³⁷ A 1990 fire deliberately started at the Happy Land Social Club in the Bronx, New York, claimed 87 victims, including a large number of nonburn deaths,⁷⁸ and the 2003 fire at the Station nightclub in West Warwick, Rhode Island, killed 98 people.¹²⁸ Carbon monoxide poisoning was a major determinant in many of these deaths, although hydrogen cyanide gas and simple asphyxiation may have also contributed to the overall mortality.

Another notable toxic gas disaster involving a fire occurred at the Cleveland Clinic in Cleveland, Ohio, in 1929, where a fire in the radiology department resulted in 125 deaths.³⁴ The burning of nitrocellulose radiographs produced nitrogen dioxide, cyanide, and carbon monoxide gases held responsible for many of the fatalities. In 2003, at least 243 people died and 10,000 became ill after a drilling well exploded in Xiaoyang, China, releasing hydrogen sulfide and natural gas into the air.¹⁵⁹ A toxic gas cloud covered 25 square kilometers. Ninety percent of the villagers who lived in the village adjoining the gas well died.

The release of a dioxin-containing chemical cloud into the atmosphere from an explosion at a hexachlorophene production factory in Seveso, Italy in 1976, resulted in one of the most serious exposures to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin {TCDD}).⁴⁹ The lethality of this xenobiotic in animals has caused considerable concern for acute and latent injury from human exposure. Although chloracne was the only significant clinical finding related to the dioxin exposure at 5-year follow-up⁹ more recent data after 30 years suggest a positive correlation between TCDD serum concentration and cancer incidence.¹⁴⁷

Air pollution is another source of toxic gases that causes significant disease and death. Complaints about smoky air date back to at least 1272, when King Edward I banned the burning of mineral coal.¹⁴² By the 19th century, the era of rapid industrialization in England, winter “fogs” became increasingly problematic. An 1873 London fog was responsible for 268 deaths from bronchitis. Excessive smog (a portmanteau of smoke and fog) in the Meuse Valley of Belgium in 1930 and in Donora, Pennsylvania, in 1948, was also blamed for excess morbidity and mortality. In 1952, another dense sulfur dioxide–laden smog in London was responsible for 4,000 deaths.⁷⁴ Both the initiation of long-overdue air pollution reform in England and the passing of the 1956 Clean Air Act by Parliament resulted from this latter “fog.”

Exposure to xenobiotics with the deliberate intent to inflict harm claimed an extraordinary number of victims during the 20th century (Table 2–2). During World War I, chlorine, phosgene, and the liquid vesicant mustard were used as battlefield weapons, with mustard causing approximately 80% of the chemical casualties.¹³⁰ Reportedly, 100,000 deaths and 1.2 million casualties were attributable to these chemical attacks.³⁷ The toxic exposures resulted in severe airway irritation, acute respiratory distress syndrome, hemorrhagic pneumonitis, skin blistering, and ophthalmic damage. Mustard was used again in the 1980s during the war between Iran and Iraq.

The Nazis used poisonous gases during World War II to commit genocide. Initially, the Nazis used carbon monoxide to kill. To expedite the killing process, Nazi scientists developed Zyklon-B gas (hydrogen cyanide gas). As many as 10,000 people per day were killed by the rapidly acting cyanide, and millions of deaths were attributable to the use of these gases.

Agent Orange was widely used as a defoliant during the Vietnam War. This herbicide consisted of a mixture of 2,4,5-trichlorophenoxy-acetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D), as well as small amounts of a contaminant, TCDD. Over the years, a large number of adverse health effects have been attributed to Agent Orange exposure. Although a 2002 Institute of Medicine study concluded that among Vietnam veterans, there was sufficient evidence to demonstrate an association between this herbicide exposure and chronic lymphocytic leukemia, soft tissue sarcomas, non-Hodgkin lymphomas, Hodgkin disease, and chloracne,⁵⁵ a 2015 critical review concluded that causation has yet to be established.¹²³

Mass exposure to the very potent organic phosphorus compound sarin occurred in March 1995, when terrorists released this chemical weapon in three separate Tokyo subway lines.¹⁰⁴ Eleven people were killed, and 5,510 people sought emergency medical evaluation at more than 200 hospitals and clinics in the area.¹³¹ This calamity introduced the spectra of terrorism to the modern emergency medical services system, resulting in a greater emphasis on hospital preparedness, including planning for the psychological consequences of such events. Sarin exposure also resulted in several deaths and hundreds of casualties in Matsumoto, Japan, in June 1994.^93,101 During the Syrian Civil War, sarin and chlorine were used on multiple occasions.⁷⁵

After the terrorist attacks on New York City in September 11, 2001, that resulted in the collapse of World Trade Center, persistent cough and increased bronchial responsiveness were noted among 8% of New York City Fire Department workers who were exposed to large amounts of dust and other particulates during the clean-up.^110,111 This condition, known as World Trade Center cough syndrome, is characterized by upper airway (chronic rhinosinusitis) and lower airway findings (bronchitis, asthma, or both) as well as, at times, gastroesophageal reflux dysfunction. The risk of development of hyperreactivity and reactive airways dysfunction was clearly associated with the intensity of exposure.¹⁶ A World Trade Center health registry was established to investigate and care for those exposed workers who may be at increased risk for development of cancer and other chronic diseases.^72,98 Registry data suggest that some workers appear to be at an increased risk for development of sarcoidosis⁵⁸ and persistent lower respiratory tract symptoms.⁵⁷

The Russian military used a mysterious “gas” to incapacitate Chechen rebels at a Moscow theatre in 2002, resulting in the deaths of more than 120 hostages. One report suggested that the gas contained a mixture of the highly potent aerosolized fentanyl derivatives carfentanil and remifentanil.¹¹⁵ Better preparation of the rescuers with suitable amounts of naloxone might have helped prevent some of these seemingly unanticipated casualties.¹⁴⁸

Ricin was found in several government buildings, including a mail processing plant in Greenville, South Carolina, in 2003 and the Dirksen Senate Office Building in Washington, DC, in 2004. Although no cases of ricin-associated illness ensued, increased concern was generated because the method of delivery was thought to be the mail, and irradiation procedures designed to kill microbials such as anthrax would not inactivate chemical toxins such as ricin.^14,124

Unintentional contamination of food and drink has led to numerous toxic disasters (Table 2–3). Ergot, produced by the fungus Claviceps purpurea, caused epidemic ergotism as the result of eating breads and cereals made from rye contaminated by C. purpurea. In some epidemics, convulsive manifestations predominated, and in others, gangrenous manifestations predominated.⁹⁰ Ergot-induced severe vasospasm was thought to be responsible for both presentations.^89,90 In 994 A.D., 40,000 people died in Aquitania, France, in one such epidemic.⁷⁰ Convulsive ergotism was initially described as a “fire which twisted the people,” and the term “St. Anthony’s fire” (ignis sacer) was used to refer to the excruciating burning pain experienced in the extremities that is an early manifestation of gangrenous ergotism. The events surrounding the Salem, Massachusetts, witchcraft trials have also been attributed to the ingestion of contaminated rye. The bizarre neuropsychiatric manifestations exhibited by some of the individuals associated with this event may have been caused by the hallucinogenic properties of ergotamine, a lysergic acid diethylamide (LSD) precursor.^23,84

During the last half of the 20th century, unintentional mass poisoning from food and drink contaminated with toxic chemicals became all too common. One of the more unusual poisonings occurred in Turkey in 1956 when wheat seed intended for planting was treated with the fungicide hexachlorobenzene and then inadvertently used for human consumption. Approximately 4,000 cases of porphyria cutanea tarda were attributed to the ingestion of this toxic wheat seed.¹²⁵

Another example of chemical food poisoning took place in Epping, England, in 1965. In this incident, a sack of flour became contaminated with methylenedianiline when the chemical unintentionally spilled onto the flour during transport to a bakery. Subsequent ingestion of bread baked with the contaminated flour produced hepatitis in 84 people. This outbreak of toxic hepatitis became known as Epping jaundice.⁶³

The manufacture of polybrominated biphenyls (PBBs) in a factory that also produced food supplements for livestock resulted in the unintentional contamination of a large amount of livestock feed in Michigan in 1973.²⁴ Significant morbidity and mortality among the livestock population resulted, and increased human tissue concentrations of PBBs were reported,¹⁵⁵ although human toxicity seemed limited to vague constitutional symptoms and abnormal liver function test results.

The chemical contamination of rice oil in Japan in 1968 caused a syndrome called Yusho (“rice oil disease”). This occurred when heat-exchange fluid containing polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) leaked from a heating pipe into the rice oil. More than 1,600 people developed chloracne, hyperpigmentation, an increased incidence of liver cancer, or adverse reproductive effects. In 1979 in Taiwan, 2,000 people developed similar clinical manifestations after ingesting another batch of PCB-contaminated rice oil. This latter epidemic was referred to as Yu-Cheng (“oil disease”).⁵⁶ These polychlorinated chemicals are very biopersistent, with follow-up testing 40 years later demonstrating blood half-lives approaching infinity in some patients.⁸⁵

In another oil contamination epidemic, consumption of illegally marketed cooking oil in Spain in 1981 was responsible for a mysterious poisoning epidemic that affected more than 19,000 people and resulted in at least 340 deaths. Exposed patients developed a multisystem disorder referred to as toxic oil syndrome (or toxic epidemic syndrome), characterized by pneumonitis, eosinophilia, pulmonary hypertension, scleroderma-like features, and neuromuscular changes. Although this syndrome was associated with the consumption of rapeseed oil denatured with 2% aniline, the exact etiology was not definitively identified at the time. Subsequent investigations suggest that the fatty acid oleyl anilide may have been the putative xenobiotic.^59,60,108

In 1999, an outbreak of health complaints related to consuming Coca-Cola occurred in Belgium, when 943 people, mostly children, complained of gastrointestinal (GI) symptoms, malaise, headaches, and palpitations after drinking Coca-Cola.¹⁰² Many of those affected complained of an “off taste” or bad odor to the soft drink. In some of the Coca-Cola bottles, the carbon dioxide was contaminated with small amounts of carbonyl sulfide, which hydrolyzes to hydrogen sulfide, and may have been responsible for odor-triggered reactions. Mass psychogenic illness may have contributed to the large number of medical complaints because the concentrations of the carbonyl sulfide and hydrogen sulfide were very low and unlikely to cause systemic toxicity.³⁹

Epidemics of heavy metal poisoning from contaminated food and drink have also occurred throughout history. Epidemic lead poisoning is associated with many different vehicles of transmission, including leaden bowls, kettles, and pipes. A famous 18th-century epidemic was known as the Devonshire colic. Although the exact etiology of this disorder was unknown for many years, later evidence suggested that the ingestion of lead-contaminated cider was responsible.¹⁴⁵

Intentional chemical contamination of food may also occur. Multiple cases of metal poisoning occurred in Buenos Aires in 1987, when vandals broke into a butcher’s shop and poured an unknown amount of a 45% sodium arsenite solution over 200 kg of partly minced meat.¹¹⁷ The contaminated meat was purchased by 718 people. Of 307 meat purchasers who submitted to urine sampling, 49 had urine arsenic concentrations of 76 to 500 mcg/dL, and 12 had urine arsenic concentrations above 500 mcg/dL (normal urine arsenic concentration is <50–100 mcg/dL).

Cases of deliberate mass poisoning have heightened concerns about food safety and security. In China in 2002, a jealous food vendor adulterated fried dough sticks, sesame cakes, and rice prepared in a rival’s snack bar by surreptitiously putting a large amount of tetramine (tetramethylene disulfotetramine) into the raw pastry material. More than 300 people who consumed these adulterated snacks became ill, and 42 died.³⁰ In Maine in 2003, a disillusioned parishioner contaminated the communal coffee pot at a church bake sale with arsenic. One victim died within 12 hours, and five others developed hypotension.¹⁵⁶ In 2003 in Michigan, 92 people became ill after ingesting contaminated ground beef deliberately contaminated with a nicotine pesticide by a supermarket employee.⁶

At the end of the 20th century and beginning of the 21st century, what may be the greatest mass poisoning in history occurred in Bangladesh and India’s West Bengal State^{33,95,112,135} (Chap. 86). In Bangladesh alone, 60 million people routinely drank arsenic-contaminated ground water, and at least 220,000 inhabitants of India’s West Bengal were diagnosed with arsenic poisoning.⁹⁴ Symptoms reported include melanosis, depigmentation, hyperkeratosis, hepatomegaly, splenomegaly, squamous cell carcinoma, intraepidermal carcinoma, and gangrene.³³ In a country long plagued by dysentery, attempts to purify the water supply led to the drilling of millions of wells into the superficial water table. Unknown to the engineers, this water was naturally contaminated with arsenic, creating several thousand tube wells with extremely high concentrations of arsenic—up to 40 times the acceptable concentration. Although toxicity from arsenic-contaminated groundwater was previously reported from other areas of the world, including Argentina, China, Mexico, Taiwan (black foot disease), and Thailand, the number of people at risk in Bangladesh and West Bengal is by far the largest. A 2016 report suggests that 40 million people in Bangladesh may still be exposed to unsafe concentrations of arsenic in the water with tens of thousands of deaths per year attributed to arsenic exposure.⁷³

Methyl mercury is responsible for several poisoning epidemics in the past half century. During the 1950s, a Japanese chemical factory that manufactured vinyl chloride and acetaldehyde routinely discharged mercury into Minamata Bay, resulting in contamination of the aquatic food chain. An epidemic of methyl mercury poisoning ensued as the local people ate the poisoned fish.^109,141 Chronic brain damage, tunnel vision, deafness, and severe congenital defects were associated with this mass poisoning.¹⁰⁹ Another mass epidemic of methyl mercury poisoning occurred in Iraq in 1971, when the local population consumed homemade bread prepared from wheat seed treated with a methyl mercury fungicide.¹⁵ Six thousand hospital admissions and more than 400 deaths were associated with this mass poisoning. As was the case of the hexachlorobenzene exposure in Turkey 15 years previously, the treated grain, intended for use as seed, was instead utilized as food.

From 1939 to 1954, contamination of the local water supply with the wastewater runoff from a zinc–lead–cadmium mine in Japan was believed responsible for causing Itai-Itai (“ouch-ouch”) disease, an unusual chronic syndrome manifested by extreme bone pain and osteomalacia. The local water was used for drinking and irrigation of the rice fields. Approximately 200 people who lived along the banks of the Jintsu River developed these peculiar symptoms, which were thought most likely to be caused by the cadmium.²

More than 50,000 infants were hospitalized in China in 2008 from the ill effects of melamine-contaminated powdered infant formulae.⁵⁴ Melamine (1,3,5-triazine–2,4,6-triamine) is a component in many adhesives, glues, plastics, and laminated products (eg, plywood, cleaners, cement, cleansers, fire-retardant paint). More than 20 Chinese companies produced the tainted formula. Analysis of these formulas found melamine concentrations as high as 2,500 ppm. Clinically, exposure to high doses of melamine has been associated with the development of nephrolithiasis, obstructive uropathy, and in some cases acute kidney failure.¹⁴⁶ Melamine contamination of pet food resulting in deaths in dogs and cats was previously reported.²² The melamine disaster also demonstrates that globalization and international agribusiness may facilitate worldwide distribution of contaminated foodstuffs. After the initial reports of melamine contamination in China, investigation in the United States revealed that certain brands of cookies, biscuits, candies, and milk sold in this country were also tainted with melamine, some of which was traced to an origin in China.⁵⁴

Illness and death as a consequence of therapeutic drug use occur as sporadic events, usually affecting individual patients, or as mass poisoning, affecting multiple (sometimes hundreds or thousands) patients. Sporadic single-patient medication-induced tragedies usually result from errors (Chaps. 1 and 135) or unforeseen idiosyncratic reactions. Mass therapeutic drug disasters have generally occurred secondary to poor safety testing, a lack of understanding of diluents and excipients, drug contamination, or problems with unanticipated drug–drug interactions or drug toxicity (Table 2–4).