2: Toxicologic Misfortunes and Catastrophes In History

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 an increasingly common event. 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 toxicity in our environment. Globalization has led to the proliferation of toxic chemicals throughout the world and their rapid distribution. Many chemical 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.³⁴ A much 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 1700 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.¹²⁹ 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 2500 deaths and 200,000 injuries.⁸⁰ 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 eye problems.³⁰ Calls for improvement in disaster preparedness and strengthened “right-to-know” laws regarding potential toxic exposures resulted from this tragedy.^48,129

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.¹³⁷

More than any other single toxin, carbon monoxide has been 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.³⁶ 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,⁷² and the 2003 fire at the Station nightclub in West Warwick, Rhode Island, killed 98 people.¹¹⁵ 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.³³ 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 Gaogiao, China, releasing hydrogen sulfide and natural gas into the air.¹⁴² 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).⁴⁷ The lethality of this xenobiotic in animals has caused considerable concern for acute and latent injury from human exposure. Despite this apprehension, chloracne was the only significant clinical finding related to the dioxin exposure at 5-year follow-up.⁹

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 sea coal.¹²⁷ 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 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 4000 deaths.⁶⁹ Both the initiation of long-overdue air pollution reform in England and Parliament’s passing of the 1956 Clean Air Act 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.¹¹⁷ Reportedly, 100,000 deaths and 1.2 million casualties were attributable to these chemical attacks.³⁴ The toxic exposures resulted in severe airway irritation, acute respiratory distress syndrome, hemorrhagic pneumonitis, skin blistering, and ocular damage. Chemical weapons were used again in the 1980s during the war between Iran and Iraq.

The Nazis used poisonous gases during World War II to commit mass murder. 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, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), better known as dioxin. Over the years, a large number of adverse health effects have been attributed to Agent Orange exposure. A 2002 Institute of Medicine study concluded that among Vietnam veterans, there is sufficient evidence to demonstrate an association between this herbicide exposure and chronic lymphocytic leukemia, soft tissue sarcomas, non-Hodgkin lymphomas, Hodgkin disease, and chloracne.⁵³

Mass exposure to the very potent organic phosphorus compound sarin occurred in March 1995 when terrorists released this chemical warfare agent in three separate Tokyo subway lines.⁹⁶ Eleven people were killed, and 5510 people sought emergency medical evaluation at more than 200 hospitals and clinics in the area.¹¹⁸ 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.^85,93

After the terrorist attacks on New York City on 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.^102,103 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 has been established to investigate if those exposed workers may be at increased risk for development of cancer and other chronic diseases.^68,90 Registry data suggest that some workers appear to be at an increased risk of developing sarcoidosis.⁵⁵

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. Although never publically indentified, the gas may have consisted of a highly potent aerosolized fentanyl derivative such as carfentanil and an inhalational anesthetic such as halothane. Better preparation of the rescuers with suitable amounts of naloxone may have helped prevent many of these seemingly unanticipated casualties.¹³¹

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.^14,111

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.⁸² Ergot-induced severe vasospasm was thought to be responsible for both presentations.⁸¹ In 994 a.d., 40,000 people died in Aquitania, France, in one such epidemic.⁶⁶ 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.^22,78

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 4000 cases of porphyria cutanea tarda were attributed to the ingestion of this toxic wheat seed.¹¹²

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.⁵⁹

The manufacture of polybromated 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 1973.²³ Significant morbidity and mortality among the livestock population resulted, and increased human tissue concentrations of PBBs were reported,¹³⁸ 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 1600 people developed chloracne, hyperpigmentation, an increased incidence of liver cancer, or adverse reproductive effects. In 1979 in Taiwan, 2000 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”).⁵⁴

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, sclerodermalike ­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.^56,57,100

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.⁹⁴ 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.³⁸

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.¹³⁰

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.¹⁰⁸ 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 µg/dL, and 12 had urine arsenic concentrations above 500 µg/dL (normal urine arsenic is <50–100 µg/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.²⁹ 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.¹³⁹ 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 the 21st century, what may be the greatest mass poisoning in history is occurring in Bangladesh and India’s West Bengal State.^{32,87,104,121} (See Chap. 89.) In Bangladesh alone, 60 million people are routinely drinking arsenic-contaminated ground water and at least 220,000 inhabitants of India’s West Bengal have been diagnosed with arsenic poisoning.⁸⁶ Symptoms reported include melanosis, depigmentation, hyperkeratosis, hepatomegaly, splenomegaly, squamous cell carcinoma, intraepidermal carcinoma, and gangrene.³² 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.

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.^101,126 Chronic brain damage, tunnel vision, deafness, and severe congenital defects were associated with this mass poisoning.¹⁰¹ 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 used 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 formulas.⁵² 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, and fire-retardant paint). More than 20 Chinese companies produced the tainted formula. Analysis of these formulas found melamine concentrations as high as 2500 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. Melamine contamination of pet food resulting in deaths in dogs and cats had previously been reported.²¹ 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.⁵²

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 140) 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).

In September and October 1937, more than 105 deaths were associated with the use of one of the early sulfa preparations—elixir of sulfanilamide-Massengill—that contained 72% diethylene glycol as the vehicle for drug delivery. Little was known about diethylene glycol toxicity at the time, and many cases of acute kidney failure and death occurred.⁴⁰ To avoid similar tragedies in the future, animal drug testing was mandated by the Food, Drug, and Cosmetic Act of 1938.¹³² Unfortunately, diethylene glycol continues to be sporadically used in other countries as a medicinal diluent, resulting in deaths in South Africa (1969), India (1986), Nigeria (1990), Bangladesh (1990–1992), and Haiti (1995–1996).¹³³ In 1996 in Haiti, at least 88 Haitian children died (case fatality rate of 98% for those who remained in Haiti) after ingesting an acetaminophen (APAP) elixir formulated with diethylene glycol–contaminated glycerin.^95,110 In Panama in 2006, glycerin contaminated with diethylene glycol found in prescription liquid cough syrup resulted in at least 121 cases of poisoning and 78 deaths (case fatality rate, 65.5%).^18,106 Investigators of this last outbreak discovered that the contaminated glycerin was imported to Panama from China via a European broker, demonstrating that improprieties in pharmaceutical manufacturing may have worldwide implications. In Nigeria in 2009, a tainted teething formula was responsible for 84 deaths in children.⁷ The pharmaceutical manufacturers intended to purchase propylene glycol, a component of the teething formula, but had bought the diluent in a jerrycan instead of the original container, and the chemical contained diethylene glycol (Special Considerations: SC7).

A lesser known drug manufacturing event, also involving an early sulfa antimicrobial, occurred in 1940 to 1941, when at least 82 people died from the therapeutic use of sulfathiazole that was contaminated with phenobarbital (Luminal).¹²² The responsible pharmaceutical company, Winthrop Chemical, produced both sulfathiazole and phenobarbital, and the contamination likely occurred during the tableting process because the tableting machines for the two medications were adjacent to each other and were used ­interchangeably. Each contaminated sulfathiazole tablet contained about 350 mg of phenobarbital (and no sulfathiazole), and the typical sulfathiazole dosing regimen was several tablets within the first few hours of therapy. Twenty-nine percent of the production lot was contaminated. Food and Drug Administration (FDA) intervention was required to assist with the recovery of the tablets, although 22,000 contaminated tablets were never found.¹²²

In the early 1960s, one of the worst drug-related modern-day events occurred with the release of thalidomide as an antiemetic and sedative–hypnotic.³¹ Its use as a sedative–hypnotic by pregnant women caused about 5000 babies to be born with severe congenital limb anomalies.⁸² This tragedy was largely confined to Europe, Australia, and Canada, where the drug was initially marketed. The United States was spared because of the length of time required for review and the rigorous scrutiny of new drug applications by the FDA.⁷⁹

A major therapeutic drug event that did occur in the United States involved the recommended and subsequent widespread use of diethylstilbestrol (DES) for the treatment of threatened and habitual abortions. Despite the lack of convincing efficacy data, as many as 10 million Americans received DES during pregnancy or in utero during a 30-year period, until the drug was prohibited for use during pregnancy in 1971. Adverse health effects associated with DES use include increased risk for breast cancer in “DES mothers” and increased risk of a rare form of vaginal cancer, reproductive tract anomalies, and premature births in “DES daughters.”^42,46

Thorotrast (thorium dioxide 25%) is an intravenous radiologic contrast medium that was widely used between 1928 and 1955. Its use was ­associated with the delayed development of hepatic angiosarcomas, as well as skeletal sarcomas, leukemia, and “thorotrastomas” (malignancies at the site of extravasated thorotrast).^120,134

The use of thallium to treat ringworm infections in the 1920s and 1930s also led to needless morbidity and mortality.⁴³ Understanding that thallium caused alopecia, dermatologists and other physicians prescribed thallium acetate, both as pills and as a topical ointment (Koremlu), to remove the infected hair. A 1934 study found 692 cases of thallium toxicity after oral and topical application and 31 deaths after oral use.⁸⁹ “Medicinal” thallium was subsequently removed from the market.

The “Stalinon affair” in France in 1954 involved the unintentional contamination of a proprietary oral medication that was marketed for the treatment of staphylococcal skin infections, osteomyelitis, and anthrax. Although it was supposed to contain diethyltin diiodide and linoleic acid, triethyltin, a potent neurotoxin and the most toxic of organotin compounds, and trimethyltin were present as impurities. Of the approximately 1000 people who received this medication, 217 patients developed symptoms, and 102 patients died.^10,17

An unusual syndrome, featuring a constellation of abdominal symptoms (pain and diarrhea) followed by neurologic symptoms (peripheral neuropathy and visual disturbances, including blindness) was experienced by approximately 10,000 Japanese people between 1955 and 1970, resulting in several hundred deaths.⁶² This presentation, subsequently labeled subacute myelooptic neuropathy (SMON), was associated with the use of the GI disinfectant clioquinol, known in the West as Entero-Vioform and most often used for the prevention of travelers’ diarrhea.⁹² In Japan, this drug was referred to as sei-cho-zai (“active in normalizing intestinal function”). It was incorporated into more than 100 nonprescription medications and was used by millions of people, often for weeks or months. The exact mechanism of toxicity has not been determined, but recent investigators theorize that clioquinol may enhance the cellular uptake of certain metals, particularly zinc, and that the clioquinol–zinc chelate may act as a mitochondrial toxin, causing this ­syndrome.¹³ New cases declined rapidly when clioquinol was banned in Japan.

In 1981, a number of premature neonates died with a “gasping syndrome,” manifested by severe metabolic acidosis, respiratory depression with gasping, and encephalopathy.⁴¹ Before the development of these findings, the infants had all received multiple injections of heparinized bacteriostatic sodium chloride solution (to flush their indwelling catheters) and bacteriostatic water (to mix medications), both of which contained 0.9% benzyl alcohol. Accumulation of large amounts of benzyl alcohol and its metabolite benzoic acid in the blood was thought to be responsible for this syndrome.⁴¹

In 1989 and 1990, eosinophilia-myalgia syndrome, a debilitating syndrome somewhat similar to toxic oil syndrome, developed in more than 1500 people who had used the dietary supplement l-tryptophan.¹²⁸ These patients presented with disabling myalgias and eosinophilia, often accompanied by extremity edema, dyspnea, and arthralgias. Skin changes, neuropathy, and weight loss sometimes developed. Intensive investigation revealed that all affected patients had ingested l-tryptophan produced by a single manufacturer that had recently introduced a new process involving genetically altered bacteria to improve l-tryptophan production. A contaminant produced by this process probably was responsible for this syndrome.²⁰ The banning of l-tryptophan by the FDA set in motion the passage of the Dietary Supplement Health and Education Act of 1994. This legislation, which attempted to regulate an uncontrolled industry, facilitated industry marketing of dietary supplements bypassing FDA scrutiny. In 2001, the FDA loosened the restrictions on the marketing of tryptophan, which is now sold through some compounding pharmacies.

A number of pharmaceuticals previously approved by the FDA have been withdrawn from the market because of concerns about health risks.¹⁴¹ Many more drugs have been given “black box warnings” by the FDA because of their propensity to cause serious or life-threatening adverse effects.⁷⁷ Some of the withdrawn drugs had been responsible for causing serious drug–drug interactions (astemizole, cisapride, mibefradil, terfenadine).⁸⁸ Other drugs were withdrawn because of a propensity to cause ­hepatotoxicity (troglitazone), anaphylaxis (bromfenac sodium), valvular heart disease (fenfluramine, dexfenfluramine), rhabdomyolysis (cerivastatin), hemorrhagic stroke (phenylpropanolamine), and other adverse cardiac and neurologic effects (ephedra, rofecoxib). One of the more disconcerting drug problems to arise was the development of cardiac valvulopathy and pulmonary hypertension in patients taking the weight-loss drug combination fenfluramine and phentermine (fen-phen) or dexfenfluramine.^27,116 The histopathologic features observed with this condition were similar to the valvular lesions associated with ergotamine and carcinoid syndrome. Interestingly, appetite suppressant medications, as well as ergotamine and carcinoid, all increase available serotonin.

Unintended toxic disasters have also involved the use of alcohol and other drugs of abuse (Table 2–5). Arsenical neuropathy developed in an estimated 40,000 people in France in 1828, when wine and bread were unintentionally contaminated by arsenious acid.⁷⁶ The use of arsenic-contaminated sugar in the production of beer in England in 1900 resulted in at least 6000 cases of peripheral neuropathy and 70 deaths (Staffordshire beer epidemic).⁵

During the early 20th century, particularly during Prohibition, the ethanolic extract of Jamaican ginger (sold as “the Jake”) was a popular ethanol substitute in the southern and midwestern United States.⁸³ It was sold legally because it was considered a medical supplement to treat headaches and aid digestion and was not subject to Prohibition. For years, the Jake was sold adulterated with castor oil, but in 1930, as the price of castor oil rose, the Jake was reformulated with an alternative adulterant, triorthocresyl phosphate (TOCP). Little was previously known about the toxicity of this compound, and TOCP proved to be a potent neurotoxin. From 1930 to 1931, at least 50,000 people who drank the Jake developed TOCP poisoning, manifested by upper and lower extremity weakness (“ginger Jake paralysis”) and gait impairment (“Jake walk” or “Jake leg”).⁸³ A quarter century later, in Morocco, the dilution of cooking oil with a turbojet lubricant containing TOCP caused an additional 10,000 cases of TOCP-induced paralysis.¹¹⁹

In the 1960s, cobalt was added to several brands of beer as a foam ­stabilizer. Certain local breweries in Quebec City, Canada; Minneapolis, Minnesota; Omaha, Nebraska; and Louvain, Belgium added 0.5–5.5 ppm cobalt to their beer. This resulted in epidemics of fulminant heart failure among heavy beer drinkers (named cobalt–beer cardiomyopathy).^1,84

Epidemic methanol poisoning among those seeking ethanol and other inebriants is well described. In one such incident in Atlanta, Georgia, in 1951, the ingestion of methanol-contaminated bootleg whiskey caused 323 cases of methanol poisoning, including 41 deaths. In another epidemic in 1979, 46 prisoners became ill after ingesting a methanol-containing diluent used in copy machines.¹²³

In recent years, major mass methanol poisonings have continued to occur in developing countries, where store-bought alcohol is often prohibitively expensive. In Baroda, India, in 1989, at least 100 people died and another 200 became ill after drinking a homemade liquor that was contaminated with methanol.⁴ In New Delhi, India, in 1991, an inexpensive antidiarrheal medicine, advertised to contain large amounts of ethanol, was instead contaminated with methanol, causing more than 200 deaths.²⁶ The following year, in Cuttack, India, 162 people died and an additional 448 were hospitalized after drinking methanol-tainted liquor.¹¹ A major epidemic of methanol poisoning occurred in 1998 in Cambodia, when rice wine was contaminated with methanol.³ At least 60 deaths and 400 cases of illness were attributed to the methanol. In 2011 in Sangrampur, India, more than 143 died from drinking methanol tainted bootleg alcohol.⁷¹

So-called “designer drugs” are responsible for several toxicologic disasters. In 1982, several injection drug users living in San Jose, California, who were attempting to use a meperidine analog MPPP (1-methyl-4-phenyl-4-propionoxy-piperidine) developed a peculiar, irreversible neurologic disease closely resembling Parkinson disease.⁶⁴ Investigation revealed that these patients had unknowingly injected trace amounts of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which was present as an inadvertent product of the clandestine MPPP synthesis. The subsequent metabolism of MPTP to MPP⁺ resulted in a toxic compound that selectively destroyed cells in the substantia nigra depleting dopamine stores or products causing severe and irreversible parkinsonism. The vigorous pursuit of the cause of this disaster led to a better understanding of the pathophysio­logy of parkinsonism.

Another example of a “designer drug” poisoning occurred in the New York City metropolitan area in 1991, when a sudden epidemic of opioid overdoses occurred among heroin users who bought envelopes labeled “Tango and Cash.”³⁷ Expecting to receive a new brand of heroin, the drug users instead purchased the much more potent fentanyl. Increased and unpredictable toxicity resulted from the inability of the dealer to adjust (“cut”) the fentanyl dose properly. Some purchasers presumably received little or no fentanyl, but others received potentially lethal doses. A similar epidemic involving 3-methylfentanyl occurred in 1988 in Pittsburgh, Pennsylvania and continue to occur in the United States in the 21st Century.⁷⁴

At least 325 cases of anticholinergic poisoning occurred among heroin users in New York City; Newark, New Jersey; Philadelphia, Pennsylvania; and Baltimore, Maryland from 1995 to 1996.⁸ The “street drug” used in these cases was adulterated with scopolamine. Whereas naloxone treatment was associated with increased agitation and hallucinations, physostigmine administration resulted in resolution of symptoms. Why the heroin was adulterated was unknown, although the use of an opiate–scopolamine mixture was reminiscent of the morphine–scopolamine combination therapy known as “twilight sleep” that was extensively used in obstetric anesthesia during the early 20th century.⁹⁸ Another unexpected complication of heroin use was observed in the Netherlands in the 1980s, when 47 heroin users developed mutism and spastic quadriparesis that was pathologically documented to be spongiform leukoencephalopathy.¹⁴⁰ In these and subsequent cases in Europe and the United States, the users inhaled heroin vapors after the heroin powder had been heated on aluminum foil, a drug administration technique known as “chasing the dragon.”^60,140 The exact toxic mechanism has not been elucidated.

Unfortunately, occupation-related toxic epidemics have become increasingly common (Table 2–6). Such poisoning syndromes tend to have an insidious onset and may not be recognized clinically until years after the exposure. A specific xenobiotic may cause myriad problems, among the most worrisome being the carcinogenic and mutagenic potentials.

Although the 18th-century observations of Ramazzini and Pott introduced the concept of certain diseases as a direct result of toxic exposures in the workplace, it was not until the height of the 19th-century industrial revolution that the problems associated with the increasingly hazardous workplace became apparent.⁵¹ During the 1860s, a peculiar disorder, attributed to the effects of inhaling mercury vapor, was described among manufacturers of felt hats in New Jersey.¹³⁵ Mercury nitrate was used as an essential part of the felting process at the time. “Hatter’s shakes” refers to the tremor that developed in an estimated 10% to 60% of hatters surveyed.¹³⁵ Extreme shyness, another manifestation of mercurialism, also developed in many hatters in later studies. Five percent of hatters during this period died from kidney failure.

Other notable 19th-century and early 20th-century occupational tragedies included an increased incidence of mandibular necrosis (phossy jaw) among workers in the matchmaking industry who were exposed to white phosphorus,⁴⁹ an increased incidence of bladder tumors among synthetic dye makers who used β-naphthylamine,⁴⁴ and an increased incidence of aplastic anemia among artificial leather manufacturers who used benzene.¹¹⁴ The epidemic of phossy jaw among matchmakers had a latency period of 5 years and a mortality rate of 20% and has been called the “greatest tragedy in the whole story of occupational disease.”²⁴ The problem continued in the United States until Congress passed the White Phosphorus Match Act in 1912, which established a prohibitive tax on white phosphorus matches.

Since antiquity, occupational lead poisoning has been a constant threat. Workplace exposure to lead was particularly problematic during the 19th century and early 20th century because of the large number of industries that relied heavily on lead. One of the most notorious of the “lead trades” was the actual production of white lead and lead oxides. Palsies, encephalopathy, and death from severe poisoning were reported.⁴⁵ Other occupations that resulted in dangerous lead exposures included pottery glazing, rubber manufacturing, pigment manufacturing, painting, printing, and plumbing.⁷³ Given the increasing awareness of harm suffered in the workplace, the British Factory and Workshop Act of 1895 required governmental notification of occupational diseases caused by lead, mercury, and phosphorus poisoning, as well as of occupational diseases caused by anthrax.⁶⁵

Exposures to asbestos during the 20th century have resulted in continuing extremely consequential occupational and environmental disasters.^28,91 Even though the first case of asbestosis was reported in 1907, asbestos was heavily used in the shipbuilding industries in the 1940s as an insulating and fireproofing material. Since the early 1940s, 8 to 11 million individuals were occupationally exposed to asbestos,⁶⁷ including 4.5 million individuals who worked in the shipyards. Asbestos-related diseases include mesothelioma, lung cancer, and pulmonary fibrosis (asbestosis). A threefold excess of cancer deaths, primarily of excess lung cancer deaths, has been observed in asbestos-exposed insulation workers.¹¹³

The manufacture and use of a variety of newly synthesized chemicals has also resulted in mass occupational poisonings. In Louisville, Kentucky in 1974, an increased incidence of angiosarcoma of the liver was first noticed among polyvinyl chloride polymerization workers who were exposed to vinyl chloride monomer.³⁵ In 1975, chemical factory workers exposed to the organochlorine insecticide chlordecone (Kepone) experienced a high incidence of neurologic abnormalities, including tremor and chaotic eye movements.¹²⁴ An increased incidence of infertility among male ­Californian pesticide workers exposed to 1,2-dibromochloropropane (DBCP) was noted in 1977.¹³⁶

A discussion of mass poisonings is incomplete without mention of the large number of radiation disasters that have characterized the 20th century (Table 2–7). The first significant mass exposure to radiation occurred among several thousand teenage girls and young women employed in the dial-painting industry.²⁵ These workers painted luminous numbers on watch and instrument dials with paint that contained radium. Exposure occurred by licking the paint brushes and inhaling radium-laden dust. Studies showed an increase in bone-related cancers, as well as aplastic anemia and leukemia, in exposed workers.^75,99

At the time of the “watch” disaster, radium was also being sold as a nostrum touted to cure all sorts of ailments, including rheumatism, syphilis, multiple sclerosis, and sexual dysfunction. Referred to as “mild radium therapy” to differentiate it from the higher dose radium that was used in the treatment of cancer at that time, such particle-emitting isotopes were hailed as powerful natural elixirs that acted as metabolic catalysts to deliver direct energy transfusions.⁷⁰

During the 1920s, dozens of patent medications containing small doses of radium were sold as radioactive tablets, liniments, or liquids. One of the most infamous preparations was Radithor. Each half-ounce bottle contained slightly more than one curie of radium-228 and radium-226. This radioactive water was sold all over the world “as harmless in every respect” and was heavily promoted as a sexual stimulant and aphrodisiac, taking on the glamour of a recreational drug for the wealthy.⁷⁰ More than 400,000 bottles were sold. The 1932 death of Eben Byers, a Radithor connoisseur, from chronic radiation poisoning drew increased public and governmental scrutiny to this unregulated radium industry and helped end the era of radioactive patent medications.⁷⁰

Concerns about the health effects of radiation have continued to escalate since the dawn of the nuclear age in 1945. Long-term follow-up studies 50 years after the atomic bombings at Hiroshima and Nagasaki demonstrate an increased incidence of leukemia, other cancers, radiation cataracts, hyperparathyroidism, delayed growth and development, and chromosomal anomalies in exposed individuals.⁵⁸

The unintentional nuclear disaster at Chernobyl, Ukraine, in April 1986 again forced the world to confront the medical consequences of 20th-century scientific advances that created the atomic age.³⁹ The release of radioactive material resulted in 31 deaths and the hospitalization of more than 200 people for acute radiation sickness. By 2003, the predominant long-term effects of the event appeared to be childhood thyroid cancer and psychological consequences.¹⁰⁵ In some areas of heavy contamination, the increase in childhood thyroid cancer has increased 100-fold.¹⁰⁹

Another serious radiation event occurred in Goiania, Brazil, in 1987 when an abandoned radiotherapy unit was opened in a junkyard and 244 people were exposed to cesium-137. Of those exposed, 104 showed ­evidence of internal contamination, 28 had local radiation injuries, and eight developed acute radiation syndrome. There were at least four deaths.^97,107

In September 1999, a nuclear event at a uranium-processing plant in Japan set off an uncontrolled chain reaction, exposing 49 people to ­radiation.⁶¹ Radiation measured outside the facility reached 4000 times the normal ambient level. Two workers died from the effects of the radiation.

A 9.0 magnitude earthquake and tsunami in Japan in March 2011 caused equipment failure at the Fukushima Daiichi nuclear plant resulted in a release of radioactive material into the atmosphere and seawater. Nearby foodstuff and drinking water were contaminated with Cesium-137 and Iodine-131.¹²⁵

Mass poisonings have also manifested themselves as events of mass ­suicide. In 1978 in Jonestown, Guyana, 911 members of the Peoples Temple died after drinking a beverage containing cyanide.¹² In 1997, phenobarbital and ethanol (sometimes assisted by physical asphyxiation) was the suicidal method favored by 39 members of the Heavens Gate cult in Rancho Santa Fe, California, a means of suicide recommended in the book Final Exit.⁵⁰ Apparently, the cult members committed suicide to shed their bodies in hopes of hopping aboard an alien spaceship they believed was in the wake of the Hale-Bopp comet.⁶³

• There are significant lessons to be learned from mass poisonings.

• An understanding of the pathogenesis of these mass poisonings pertaining to drug, food, and occupational safety is critically important to prevent future disasters.

• Such events make us aware that many of the toxic xenobiotics involved are potential agents of opportunity for terrorists and others who invoke harm.

• Given the practical and ethical limitations in studying the effects of many specific xenobiotics in humans, lessons from these unfortunate tragedies must be fully mastered and retained for future generations.

References