Wall 1 Ryan Wall Arsenic Trioxide Arsenic has a long and storied history that has rightfully earned it the moniker “The Poison of Kings and King of Poisons.” While Arsenic is an element (therefore disqualifying it from being a “molecule that changed history”), one of its most prevalent compounds, Arsenic Trioxide ( As 2 O 3 ), is highly toxic and has been used for centuries as a poison. This unassuming compound is a white powder, is odorless, and is tasteless. However, it has taken countless lives, whether by direct ingestion or accidental exposure. While arsenic trioxide has a dark past, it also has contributed to society as well by paving the way for urbanization and offering relief to leukemia patients. This contradictory history has made arsenic trioxide quite the controversial molecule, a legacy that continues to this day. Molecular Structure
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Ryan Wall
Arsenic Trioxide
Arsenic has a long and storied history that has rightfully earned it the moniker “The
Poison of Kings and King of Poisons.” While Arsenic is an element (therefore disqualifying it
from being a “molecule that changed history”), one of its most prevalent compounds, Arsenic
Trioxide ( As2O3), is highly toxic and has been used for centuries as a poison. This unassuming
compound is a white powder, is odorless, and is tasteless. However, it has taken countless lives,
whether by direct ingestion or accidental exposure. While arsenic trioxide has a dark past, it also
has contributed to society as well by paving the way for urbanization and offering relief to
leukemia patients. This contradictory history has made arsenic trioxide quite the controversial
molecule, a legacy that continues to this day.
Molecular Structure
Arsenic Trioxide comprises of two Arsenic atoms covalently bonded to three Oxygen
atoms (Cassarett, 1999). While it is primarily referred to as arsenic trioxide, it can also be called
Arsenic (III) Oxide, Arsenic sesquioxide, Arseneous oxide, Arseneous anhydride, and White
arsenic. Arsenic trioxide can be formed by roasting arsenic ores, called realgar, and purifying the
smoke. It is primarily obtained as a by-product of ore mining; China is the only country in which
it is intentionally mined (“Mineral Resources of the United States”). Naturally, China is the
leading producer of arsenic trioxide, followed by Chile and Peru. The United States is the
world’s leading consumer of products containing arsenic trioxide. This has led to several
accidental deaths as miners are exposed to it daily. The molecule resembles sugar, coming in
either a fine wide powder or small clumps (Chemical Book). It is slightly soluble in water and
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dissolves very slowly at room temperature; it is highly soluble at higher temperatures. Arsenic
trioxide is noncombustible and is corrosive to metals in the presence of moisture. When burned,
it will release toxic fumes.
A toxic dosage for the average human is less than 5 mg/kg – practically a taste – which
explains why it is so prevalent in murders (Williams, 2011). Once ingested orally, arsenic
trioxide will attack the nervous system and affect the gastrointestinal system, kidney, and liver.
This causes severe abdominal and muscular cramps, diarrhea, vomiting, and ultimately death.
Symptoms of external exposure include nasal septum perforations and skin conditions like
lesions, dry skin, redness, and necrosis. If exposed to the eyes, arsenic trioxide can cause
conjunctivitis and deep burns. Most notably, arsenic trioxide is a carcinogen, and has shown to
increase likelihood of getting lung and lymphatic cancers. Whenever an individual comes in
contact with arsenic trioxide, whether through ingestion or exposure, symptoms are typically
delayed; typically at least half an hour to an hour after initial exposure (Chemical Book)
Rodenticide
Perhaps one of the earliest uses for arsenic trioxide was as a rodenticide. Its use dates
back to Elizabethan England (History Magazine). In the 1500s, arsenic trioxide was sold as
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“ratsbane” and was the most popular way to combat a growing rodent problem. In fact, it had
become so engrained in pop culture that Shakespeare included a reference to the poison in Henry
IV, Part II (“I had as lief they would put ratsbane in my mouth as offer to stop it with security").
Rats had plagued Europe for hundreds of years: they were natural disease spreaders and posed a
huge threat to a rapidly expanding urban population.
London’s rodent problem festered throughout the century, precipitating a disastrous
outbreak in 1665 (Trueman, 2015). The Plague of 1665 killed thousands of Londoners, and
rodenticides made from arsenic trioxide helped quell the rat population. However, the plague
was so bad that it was not until the Great Fire of 1666 that the rat problem was finally brought
under control. However, it was never really “under control.” Rodenticides containing arsenic
trioxide continued to remain popular as a means of managing the rat population in Europe. As
more and more cities popped up across the continent, rats began to spread as urban sewage
systems emerged and expanded (History Magazine). Beginning in the 1850s, after centuries of
struggling to control public sewage, Paris built “Les egouts,” an ambitious sewer system that was
intended to encompass the entire city. A rodenticide containing arsenic trioxide eventually
helped get the problem under control. Use of these rodenticides continued well into the twentieth
century. Alternative poisons that are less dangerous to humans have since been developed, but
arsenic trioxide played a vital part in controlling the rat population and curbing the spread of
deadly epidemics.
The Rise of Inheritance Powder
Arsenic trioxide is perhaps most notable as the go-to poison of the Victorian Era (Haslan,
2013). The tasteless powder that was fatal in small dosages was very easy to slip into a beverage.
After it dissolved, it was impossible to detect until the fatal sip had been taken. Because of this,
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arsenic trioxide quickly reached notoriety as “Inheritance Powder” (Hempel, 2013). It earned this
nickname because greedy children could use the powder to poison their parents and inherit the
estate. This was the case of Mary Ann Cotton, a Sunday school teacher from England (Haslam,
2013). Between 1852 and 1872, Cotton killed over twenty people with arsenic, and in each case
the victim was believed to have been killed due to “gastric distress.” Her laundry list of victims
included four husbands, ten children, five stepchildren, her mother, her sister, a lover, and she
was suspected of many more murders. In every
case, Cotton was the recipient of an insurance
policy. It took authorities many years to catch her
due to the high mortality rates in the mining
community where she lived.
The feasibility of this method of murder
catapulted arsenic trioxide into the canons of literature, with several prominent works of fiction
relying on the chemical as a plot device (“Arsenic and Old Lace,” several Agatha Christie
novels, the list goes on). Even Mary Ann Cotton was immortalized in a nursery rhyme. Arsenic
trioxide’s prominence in the household- in rodenticides, pesticides, and animal dips- made it the
perfectly accessible tool for murder by a bitter business partner or jilted lover. Victims often
didn’t recognize the symptoms of arsenic poison (if they did at all) until it was too late.
In the case of iconic novelist, Jane Austen, that may have been the case (Jabr, 2011). Her
mysterious and abrupt death at age 41 baffled doctors, who thought that she died of Addison’s
Disease, tuberculosis, or Hodgkin’s disease. However, in 2011, nearly 200 years after her death,
crime writer Lindsay Ashford speculated that Austen had been murdered after it was discovered
that Austen’s hair had tested positive for arsenic levels. Speculations abounded; had one of the
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greatest writers of all time fallen victim to some kind of grand murder drama? It is incredibly
difficult to say. Austen’s name had not been published with her books prior to her death as a
means of modesty (Flood, 2011). Thus, her medical records and private life were just that-
private. But careful examination of her final letters and journal entries showed a steady
progression of symptoms indicative of arsenic poisoning. She avoids going into extensive detail
and refers to her condition as her “sad complaint.”
In letters to her niece, Austen described her “raindrop pigmentation,” which, along with
her other symptoms, Ashford had cited as her main warrant for her shocking suggestion. Chronic
arsenic trioxide exposure can affect melanin rates in the skin, leading to this type of spotty
complexion. Ashford argued that due to arsenic trioxide’s ubiquity in the Victorian Era, it was
entirely plausible. In Austen’s case, the author had been beset by several maladies and had to
take many arsenic-laden medicines to combat her rheumatism. Ashford believes that doctors
possibly prescribed Austen this medicine, unknowingly hastening her demise. Despite Ashford’s
claims, she acknowledged that further forensic investigation would be impossible without
disinterring the author. Whether the claims are true or not, the possibility that Austen could have
been subject to arsenic poisoning further shows how easy it was to fall victim to the powder that
was seemingly inescapable.
A Color to “Dye” For
Despite its inherent toxicity, Arsenic Trioxide began to emerge as an ingredient in several
important dyes. In 1775, chemist Carl Scheele discovered copper arsenite (CuHAsO3 ), which
was produced a light yellow-green pigment later known as Sheele’s green (Ingles-Arkell, 2015).
Scheele was a brilliant pharmaceutical chemist who history seems to have forgotten. Author
Isaac Asimov nicknamed him “Hard Luck Scheele,” because Scheele made several chemical
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discoveries without receiving due credit. In one case, his publication announcing his discovery of
oxygen was delayed, allowing Joseph Priestly to publish his paper first, thus leading many in the
scientific community to acknowledge Priestly as its sole discoverer.
Scheele’s green is closely related to the pigment produced from copper (II) acetoarsenite,
which results from the combination of copper (II) acetate and arsenic trioxide. It was first
prepared around 1814 and was used in many of the same products. In fact, they are so similar
that several historical documents use them interchangeably (Williams, 2011).
Copper (II) acetoarsenite is a pigment commonly referred to as “Paris Green,” a nod to its
original use as a rodenticide in the sewers of Paris. Despite its humble origins, Paris Green has
several ties to high-society: painters like Picasso, Cezanne, Renoir, Manet, Monet, and Seurat all
used it in some of their most famous works (“Paris Green”). Moreover, upper class women in
Europe began to wear green dresses dyed with the pigment. They also powdered their face with
arsenic trioxide to appear paler, which was then very much en vogue. All of this exposure led to
diseases and open sores, which were some of the symptoms of arsenic poisoning. The upper-
class was so fixated on aesthetic that suffering for fashion became accepted to the point that the
satirical magazine Punch deemed the practice “The Arsenic Waltz” in a widely-published
etching.
Scheele’s Green [copper arsenite] Paris Green [copper(II) acetate triarsenite]
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While Paris Green was
widely accepted as the go-
to green dye, it was used
more prominently in green
wallpaper (Williams,
2011). Over the nineteenth
century, British demand for
Paris Green wallpaper
increased steadily, reaching
its peak in 1870 with nearly 30
million rolls printed annually.
At one point, historians believe that nearly four out of every five houses in Britain used Paris
Green wallpaper; it’s no surprise that Britain remained its principal producer and consumer. This
prominence led researchers to hypothesize that wallpaper could negatively affect the atmosphere
in the room. In 1815, German chemist Leopold Gmelin noticed an odor that damp wallpaper
gave off (Meek). He hypothesized that breathing in these odors could be deleterious to one’s
health. Over the century, several other chemists and doctors ran similar tests and advocated
against Paris Green wallpaper, but these warnings fell on deaf ears as the wildly popular color
began to appear on walls throughout the world.
Interestingly enough, the most famous historical use of arsenic-based wallpaper occurred
nowhere near Britain, nor in Paris. Halfway across the world, on the remote South Atlantic island
of St. Helena, servants at a small dwelling known as the Longwood House put up some
wallpaper to welcome their newest resident: the exiled emperor of France, Napoleon Bonaparte.
The Arsenic Waltz: The delicate dance between high fashion and high exposure to toxic dyes
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This particular wallpaper was marketed as Emerald Green- surely a color worthy of the infamous
general (Williams, 2011). Napoleon arrived at the end of 1815, mere months after Gmelin had
proposed the fatal properties of arsenic-based wallpaper. In the tropical and humid climate of St.
Helena, the odors from the wallpaper would have been unbearably strong, leading Napoleon to
be poisoned slowly.
Napoleon died in 1821, and doctors officially declared his cause of death as stomach
cancer. However, accounts at the time from his personal physician and members of Napoleon’s
retinue described symptoms that didn’t align with cancer. Over a century later, the diary of
Napoleon’s valet was published, and historians and doctors noticed that Napoleon’s deteriorating
health sounded very similar to poisoning. In 1961, a Swedish toxicologist named Sten
Forschufvud performed an analysis on one of
Napoleon’s hairs (his servants had trimmed some
following his death; a rather disgusting and
interesting memento of their former master). He
found high levels of arsenic in the emperor’s hair.
However, this was not uncommon, given the ubiquity
of arsenic-based materials in the early Victorian era.
With that, the mystery surrounding the death
thickened.
When Forschufvud published his findings, it
caught the attention of chemist David Jones. Jones
had studied the how the gases emitted from green
wallpaper had fatal effects in certain conditions. He
Letter featuring wallpaper from Napoleon’s chambers in Longwood House
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began to wonder if Paris Green wallpaper had been used in Longwood House. On a radio
appearance, he mentioned it in passing, and to his surprise, received a letter from a listener a few
months later. The letter contained a sample of the wallpaper from Longwood House from the
listener’s ancestor’s trip to St. Helena in 1823. Jones tested the paper, and found it was laden
with arsenic. When he published his findings in 1982, it was met with much controversy. In a
2008 analysis, researchers found that Napoleon’s wife, Josephine, also had very high levels of
arsenic in her system (Williams, 2011). They also found that the arsenic levels in Napoleon’s
body did not suggest a rapid rise in concentration following his exile. To this day, it is unsure if
Napoleon died solely due to arsenic poisoning, but whether or not the exposure was fatal, it still
severely contributed to his failing health towards the end of his life. As in the case of Jane
Austen, it is very difficult to definitively determine whether or not Napoleon died of arsenic
poisoning without disinterring his body and running extensive forensic analysis, which would
likely prompt public outcry.
Eventually, as with other dyes, industrialization later led to the discovery of synthetic
alternatives that were markedly safer. With the rise of these synthetic dyes, use of Paris Green
began to wane. By the 1890’s, green had given way to mauve as the color of choice, with
historians later referring to the time as the “Mauve Decade” (Le Couter & Burreson, 2003).
Though it was no longer the fashionable color, companies still sold the toxic Paris Green
products well into the twentieth century.
Environmental Uses
Similar to Paris Green is London Purple, another arsenic-based dye that became quite
popular in the nineteenth century (Meek). As a dye, London Purple was never quite as popular as
its emerald cousin. However, it was frequently used as an insecticide. Paris Green consisted of
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52% Arsenic Trioxide, 42% Copper Oxide, and water, while London Purple consisted of 41%
Arsenic Trioxide, 24% Lime, 27% Dye, water and trace amounts of Alumina, Iron Oxide, and
Sulphuric Anhydride (Mineral Resources of the United States). In 1867, Paris Green was shown
to kill the Colorado potato beetle; London Purple was used soon after. This led to nearly thirty
years of arsenic-based insecticides before synthetic alternatives were discovered around the turn
of the twentieth century. London purple was the preferred alternative to Paris Green as an
insecticide because it was easy to spray and it dyed the plants a pale purple color, making it
obvious to farmers when they needed to be sprayed again. However, it would occasionally kill
the plants as well, which frustrated farmers greatly. Interestingly, as fashion ushered in the
“Decade of Mauve” in the 1890’s, London Purple began to be used more sparingly. It was soon
replaced by lead arsenate and calcium arsenate, which particularly effective against the Gypsy
Moth, a pest that had plagued farmers in New England for decades.
While the World Health Organization recognizes arsenic trioxide as an obsolete pesticide,
it continues to have an environmental impact (Environmental Health & Medical Education). The
Environmental Protection Agency currently
recognizes it as a Hazardous Air Pollutant.
There is currently an EPA Superfund site in
southeast North Dakota specifically
dedicated to arsenic trioxide. It covers 26
towns and over 936 square miles of
sparsely-populated farmland (roughly five
times the size of Philadelphia but with a
population of 1000-5000) (EPA Superfund The Arsenic Trioxide Superfund Site, Richland
and Sargent Counties, North Dakota
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Program). During the 1930s and 1940s, farmers used pesticides to combat an infestation of
grasshoppers. Unused or leftover pesticides were buried or dumped in pits. After decades of
arsenic trioxide-laced pesticides, the shallow aquifer in the area became highly contaminated.
After years of cleaning, the EPA took the land off its National Priorities List in July of
1996, following extensive work to build a water redistribution pipeline and educate the public.
However, it still impacts life in that area to this day: homeowners in those counties still have to
abide by strict guidelines to ensure they consume water safely. They need to be careful when
drinking well water, get their water tested regularly, and are advised to only consume water that
has been treated from a newly-built water treatment facility. Now, the arsenic level in the aquifer
is equivalent to a few drops of ink in an Olympic-sized swimming pool, but it still requires
attention to prevent illness after prolonged exposure. Arsenic contaminated water is found all
over the world, and third-world countries like Bangladesh struggle to battle this huge problem.
Despite this toxicity, it is quite possible that every single child has come in contact with
arsenic trioxide, as it is found in thousands of playgrounds across the United States
(“Biomonitoring Summary”). Arsenic trioxide is still used as a wood preservative, as it is a key
ingredient in copper chromated arsenate (CCA). It accounted for nearly 90% of all arsenic
An easy way to identify wood treated with CCA is through its greenish color, as seen here.
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trioxide use in the early 2000’s. When consumers learned of this, many feared that their children
could become sick.
Before long, manufacturers voluntarily began to transition to other wood treatment
products. As of December 31, 2003, the EPA helped pass legislation making it illegal to treat
lumber in residential applications with CCA. Though this legislation sought to eliminate CCA
from American timber, it was impossible to remove it entirely; to do so would require a huge
investment in infrastructure, so all pre-2003 structures could still contain wood treated with
CCA. These structures are found in decks and playgrounds across the country, and millions of
people around the world interact with them daily. However, studies have shown that there is little
difference in the arsenic levels of children who play on CCA-treated playgrounds as opposed to
children who play on CCA-free playgrounds.
Public shift away from arsenic trioxide-based products extends far beyond the
playground. For years, arsenic trioxide was the principal ingredient in animal dips (Chemical
Book). These liquids are used to protect livestock (primarily cattle and sheep) from parasites by
spraying the animal with a concoction of pesticides; this concoction typically is laden with
arsenic trioxide. The animal is literally plunged into a pool of the chemical, and it protect against
ticks, flies, mites, and lice. The practice of animal dipping helped shape the livestock industry in
the American West as animals were able to live longer and more animals were able to be raised
together. Eventually, like the dyes of the Victorian Era, synthetic alternatives replaced arsenic-
based animal dips and by the 1980’s, synthetic dips were the norm (Chemical Book)
The practice of animal dipping also led to the prominence of Temple Grandin. Grandin is
an autistic animal rights activist who is a professor at Colorado State University. In the 1970’s,
she pioneered a process to make animal dipping more humane and simple for the animal. She
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used her newfound success to transition into a career championing animal rights and advocating
for autism (In fact, she rose to such prominence that in 2010 a biopic was made on her life; it
went on to win an Emmy and Peabody Award). Grandin has appeared on numerous programs
and has authored several articles to show that autistic people can still live full, productive lives.
If Temple Grandin had never pioneered the dipping industry, she might not have found her
platform as an activist; in this way, arsenic trioxide has contributed, in part, to increased
awareness of autism.
Medicinal Use
Perhaps the greatest contradiction about arsenic trioxide is that, despite its status as the
“King of All Poisons,” it is now being used as a medicine to combat leukemia. However, it had
much earlier applications as a medicine. In the eighteenth century, Thomas Fowler created a
solution of potassium bicarbonate-based arsenic trioxide that would later bear his name as
“Fowler’s Solution” (Gibraud & Jaoven, 2010). It was prescribed as a general tonic from 1786
to 1936 and was believed to reduce white blood cell counts. Fowler’s solution was also used as a
treatment for cholera, syphilis, and malaria (which, ironically enough, had led to the discovery of
Mauve and the decrease in the popularity of Paris Green). Some say that Charles Darwin was a
frequent user. Pharmacological texts from the 1880s listed arsenic trioxide as a treatment for
hypertension, bleeding gastric ulcers, heartburn, and chronic rheumatism (which Jane Austen had
suffered from) (Jabr, 2011). In 1910, arsenic trioxide-based medicines were bolstered by Nobel
laureate Paul Ehrlich developed salvarsan, an organic type of arsenic that was used for syphilis
and trypanosomiasis. All arsenic-based medicine had unintended side effects after long periods
of exposure, which led to its quick decline in popularity as a medical panacea (Antman, 2001).
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Recently, scientists have slowly began to turn to arsenic trioxide as a means of treating
leukemia. In the 1930s, doctors noted the hematological use of arsenic trioxide in the treatment
of chronic myelogenous leukemia (CML). Until chemotherapy emerged decades later, arsenic
trioxide after radiation was considered the most effective cure for this disease (Antman 2011). In
the 1990s, Chinese reports have suggested that arsenic trioxide could also be used in both de
novo and relapse cases of acute promyelocytic leukemia (APL); one report even asserted that
arsenic trioxide monotherapy produced total clinical responses in 90% of patients with relapsed
APL. As a result of these findings, researchers began to reinvestigate the potency of arsenic
trioxide.
Studies were conducted in the United States, and in 2000, arsenic trioxide was the topic
of an international meeting of experts in New York. The meeting, titled, “The Promise of
Trisenox: Charting an Appropriate Scientific and Clinical Course,” discussed possible future
uses (Antman, 2001). The title referred to Trisenox, a form of arsenic trioxide that was being
reviewed by the Food and Drug Administration. Trisenox contains a 1.0 mg/mL concentration of
arsenic trioxide dissolved in a sterile water solution. Months after the meeting, in September, the
FDA officially approved Trisenox as a
treatment for APL, multiple mylenoma,
and myelodysplastic syndromes.
Trisenox is taken intravenously and
carries a laundry list of potential side
effects, many of which are less severe
variants of exposure from arsenic
poisoning (Antman, 2001). Because of arsenic’s toxic qualities, Trisenox is considered a bit
Trisenox is administered as an injection
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controversial, and prescriptions are very closely monitored and must be administered by a
physician. It is interesting to note that on Trisenox’s own website, the pharmaceutical company
even states that, “the mechanism of action in Trisenox is not fully known” (Trisenox). Despite
this uncertainty, doctors are still hopeful that further research will allow for a more thorough
understanding of the medicine and can help save many more lives.
Conclusion
Through its varied uses, it is apparent that Arsenic Trioxide is a molecule that has shaped
the course of history. It is difficult to think that such a toxic chemical once existed in such
ubiquity. From the sewers of Paris to the playgrounds of America, it is a compound that has
fundamentally shaped our tastes, practices, and health, but the average person barely knows of its
existence. Though it is used now considerably less than it has in the past, arsenic trioxide will
continue to impact the world in the years to come as we deal with repercussions of its past use
and study its potential applications. With it dark past and unknown future, Arsenic trioxide is
indeed the “King of All Poisons.”
References
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Antman, K. (2001, February 21). Introduction: The History of Arsenic Trioxide in Cancer