Mendoza, David BIO 345 Su II 12 Arsenic: Toxicological Contradiction Arsenic is a metalloid with a storied history and an interesting future.

. It is best known for its role as a treacherous poison from ancient times. In fact, arsenic continued to be used a murder weapon through the nineteenth century. Despite the deadly connotation attached to its name, arsenic has also achieved notoriety for its role as a medicine. Physicians as far back as Hippocrates have used it to treat ulcers, syphilis, and other ailments. In the present day, arsenic has been found to both cause cancer as well as treat it. Both a toxicant and a therapy, its character continues to be a toxicological contradiction. The first note in this treatment of arsenic is that it is not actually poisonous in its most stable elemental form. Although elemental arsenic is uncommon to begin with, it can be found in small amounts, and it is generally not toxic. For example, mountaineers in Tyrol and Styria (located in Austria), and the Alps of Switzerland used to eat relatively large quantities of pure arsenic from exposed rocks. They believed that it increased weight, strength, appetite, and endurance at high altitudes. A handful of blackish gray crystalline material (one or two grams)called arsenwould be scooped from an open rock and swallowed, or spread over bread and butter and eaten. Visitors to these areas would note that these mountaineers were generally looking very well, cherry-cheeked and strong (Schroeder, 1974, p. 98). Since the mid-twentieth century, however, this practice has been abandoned for reasons we will explore later (Schroeder, 1974, p. 98). The arsenic found in these Austrian rocks was gray arsenic, but elemental arsenic can be found in other forms because of its allotropic nature. Allotropic elements display different

physical and chemical characteristics because their atoms can assume more than one bonding arrangement. Carbon exists in three allotropic forms: graphite, diamond, and fullerene. Arsenic exists as six known allotropes . As mentioned, the most stable is gray arsenic, which is a brittle, steel-gray solid and nontoxic (Masters, 2012). However, another allotrope, yellow arsenic, exists as a gas at room temperature, and it is highly volatile and extremely poisonous (Fairhall, 1957, p. 17). Nonetheless, the vast majority of arsenic exists in combination with other elementsin arsenical formas oxides, sulfides, arsenides, sulforarsenides, and arsenites. Arsenic is capable of holding a wide range of oxidation statesfrom -3 to +5therefore, it capable of forming a variety of different compounds. The most important of these, both industrially and toxicologically, are the oxides of arsenic (arsenic (As), 2012). In fact, arsenic as a label most often applies to arsenic trioxide (which exists as As2O3 or As4O6)not elemental arsenic, which is rare in comparison. Arsenic trioxide, or arsenious oxide, is commonly referred to as white arsenic. This is the form of arsenic that has garnered the elements association with poison (Von Oettingen, 1958, p. 239). Arsenious oxide is an effective killer, used extensively as rodenticide and insecticide, and famously, for homicide. By itself, arsenious oxide exists as white, or transparent, glassy lumps or crystalline powder (Von Oettingen, 1958, p. 239). In aqueous solution, it is almost tasteless and colorless. According to Polson and Tattersall (1959), it can be administered without arousing the suspicions of a victim (p. 188). They provide accounts from the nineteenth centurya time when arsenic was a popular poisonwhich state that the compound is actually slightly sweet and nearly imperceptible. Its lack of taste, color, and odor when mixed with food or drink made white arsenic ideal as a poison (Smith, 2012). On the other hand, its main

drawback was its solubility. In cold water, arsenious oxide is only soluble in a ratio of 1:65but like most compounds, it exhibits greater solubility in hot water. As such, white arsenic has been dangerously stirred into tea or coffee. In fact, 80 milligrams of arsenious oxide will dissolve in an ounce of boiling water. Upon cooling, however, the arsenic precipitates out to form a somewhat gritty deposit (Polson & Tattersall, 1959, p. 188). Only 25 percent of the compound will remain dissolved in solution at this point. Therefore, whether it is used in tea or hot chocolate, after a few minutes, the accumulation of gritty deposit in the cup will likely attract attention. To mitigate this, poisoners learned to boil the white arsenic with the chocolate, allowing more of it to remain suspended and a larger dose to be administered. White arsenic is less effective in milky tea or cold beer because the presence of organic matter further reduces its solubility (Polson & Tattersall, 1959, pp. 188-189). After a victim ingests arsenious oxide, the symptoms it produces conveniently resemble those of food poisoning or cholera. The toxicological picture is dominated by gastrointestinal disturbances: severe gastric pain, vomiting (often blood-filled), bloody diarrhea, and gas accumulation. At first glance, these symptoms cannot clearly be connected with purposeful poisoning. However, white arsenic also affects the immediate epithelium with which it comes into contactwhether it the skin of the hand or the tongue of some tea-sipping victim. In the latter case, ingestion may be followed by a burning sensation in the oral cavity and corrosion of the lips. Often the victims breath has a garlic-like odor as well. As the poison passes into his body, symptoms worsen and his face becomes swollen and cyanotic. He begins to suffer from severe prostration. The twentieth century toxicologist for the U. S. Public Health Service, Dr. W. F. von Oettingen (1958), describes the subsequent progression to death as follows:

His skin becomes cold and clammy [shock], his body temperature decreases, and he suffers from cramps in the calves and hands because of dehydration. The pulse becomes rapid, irregular, and thready; there is precordial distress, hiccup, and gradually, sometimes suddenly, the patient passes into collapse. In the final stage of acute arsenic poisoning the respiration becomes labored, the patient loses consciousness and dies from circulatory failure and prostration. (p. 240) Acute arsenic poisoning may also manifest itself in nervous system symptoms, but not always. These occur most frequently following rapid absorption of the poison. For example, the victim may become restless and fearful, feel oppression in the chest, and/or constriction in the esophagus, among other symptoms. As the case progresses, arsenic poisoning is also known to produce injuries to the peripheral nerves, leading to peripheral paralysis (Von Oettingen, 1958, p. 240). The time frame of symptoms for such a poisoning is quite variable, depending on the individual and the dose. Initial symptomsreferring to the severe vomiting, abdominal pain, and diarrheado not usually commence until a half-hour or several hours after ingestion. As such, the resemblance to food poisoning is noteworthy. However, the variability in the onset of shock is extreme. It may develop with an hour after ingestion or at any time during the following four or five days. In fact, shock may set in suddenly in severe cases, even before vomiting and diarrhea have started (Bensley & Joron, 1963, p. 62). Unlike many modern toxicants, whose lethal doses have been estimated solely from animal data, the accepted lethal dose numbers for arsenious oxide are also rooted in data from human exposure. The lethal dose has been stated to be as low as 2 grains (130 mg). However, many cases have been recorded in which individuals have survived exposure to this amount

(Polson & Tattersall, 1959, p. 189). In their toxicological discussion, Legal Medicine, Gonzalez, Vance, Helpern, and Umberger (1954) found the lethal dose to be higher, at 3 grains (195 mg), even it is spread out over two days in two doses (p. 512). From rat experimentation, the LD50 value for arsenious oxide has been derived to be 4.5 mg/kg (Thirunavukkarasu, Viraraghavan, Subramanian, & Tanjorep, 2002, p. 416). For a 160-lb. person, this equates to a 315 mg dose. Arsenious oxide has been recognized as a poison since pre-Christian times (Polson & Tattersall, 1959, p. 188). From the Romans to the Persians, arsenic was known as the King of Poisons, as well as the Poison of Kings (Newman, 2005). Poisoning was widely seen as a means to an inheritance by royals and nobles in times past. In fact, the Roman dictator Lucius Cornelius Sulla issued the Lex Cornelia, arguably the first law against poisoning, in 82 B. C. to stem an epidemic of homicides by poisoning (Smith, 2012, para. 7). Dubbed inheritance powder in France, white arsenic was among the most ubiquitous agents for this purpose (Smith, 2002). Dr. Henry Schroeder (1974) stresses its popularity as a poison: it provides such a simple, inexpensive, and convenient vehicle in the art of homicide that the word arsenic has become synonymous with poison (p. 97). The most notorious poisoners of the Middles Ages were arguably the Borgias. The family duo of Pope Alexander VI and his son, Cesare, were experts in the applied toxicology of arsenic. Pope Alexander VI would purposefully appoint wealthy clergyman to cardinal and encourage them to increase their wealth through the Church. Then the Pope would summon these cardinals for a meal accompanied with spiked wine. Inevitably the rich cardinals would succumb to the Borgias doctored drinks and pass on their estates to the pontiffrightfully, by Church law. The Borgias became two of the wealthiest men in all of Italy by their ruthless exploitation of the toxic effects of white arsenic (Smith, 2012, para. 10-13).

Arsenic is also historically connected to the death of the famed French emperor Napoleon Bonaparte. For decades, it had been believed that Napoleon had been another victim of arsenic poisoning due to the fact that high levels of arsenic were found posthumously in hairs from Napoleons head. The theory had two explanations: first, that he was intentionally poisoned by his British captors; second, that the wallpaper in his bedroom contained arsenic and poisoned him over time. The suggestion for the latteraccidentalcase was that mold on the wallpaper slowly transformed its arsenic-based dye into poisonous fumes (Broad, 2008, para. 1-2). Let us address the toxicity of arsenic-based dye before we go further into Napoleons case. In addition to arsenious oxide, other arsenicals of industrial and toxicological significance are the arsenical pigments. Arsenic forms several inorganic green pigments. Examples include Schweinfurt and Paris green (copper acetoarsenite). These pigments were common components of wallpaper in Napoleons time. Individuals who handled these chemicals sometimes suffered from lesions on the scrotum, groin, and nasolabial fold. These lesions are characterized by erythema (development of red papules), edema (fluid accumulation), and prurigo (itchy eruptions of the skin). If arsenical pigments are ingested, they harm victims in the same way that arsenious oxide does: gastrointestinal disturbance, shock, renal compromise, and death (Von Oettingen, 1958, p. 242). Poisoning by arsenicals is most common by ingestion, but inhalation of arsenical dust is sometimes the route of absorption. Once in the body, the distribution of arsenicalswhether arsenious oxide or arsenical pigmentsdepends on the rate of poisoning. In cases of acute poisoning, most of the arsenical flows into the liver and kidneys, where it is stored. In contrast, chronic exposure to arsenicals results in a more even distribution across the tissues. One interesting feature of arsenical storage in the body, which has special medico-legal importance, is

that it also remains stored in hair, nails, and bones for long periods. Actually, once it is deposited in hair or nails, arsenic is fixed there permanently. It can only be removed from the body by cutting the hair and nails. Hair follicles can show traces of arsenic as soon as 12 hours after poisoning, but are generally detected only after a week. Moreover, determining the content of arsenic on different segments of a length of hair or nail can elucidate how many separate doses of arsenical have been absorbed and when each was absorbed relative to one another. For example, given that hair grows at a rate of about 1/2 inch per month, two traces of arsenic found on a hair separated by 2 inches indicate that the second dose of arsenical was absorbed four months after the first (Polson & Tattersall, 1959, p. 191). Returning to the arsenic discovered in Napoleons hairs, scholars and scientists previously believed that these traces implied his death was due to arsenic poisoning. However, in 2008, a team of scientists at Italys National Institute of Nuclear Physics decided to cast a wider net on this hair analysis. They tested hairs taken from Napoleons head at four times in his life (as a boy, at age 45, and two at age 51the day he died and the following day). The team discovered that all of these samples demonstrated the same high levels of arsenic. Moreover, after they tested the hair of his wife, Empress Josephine, and his son, Napoleon II, for comparison, they found high levels of arsenic again. Thus, the Italian scientists debunked the theory that blamed Napoleons death on arsenic poisoning. Instead, they attributed the elevated traces of the toxicant in the emperors hair to arsenics success in Napoleons time as a fashionable medicine (Broad, 2008, para. 5-12). Ironically, even though arsenic is synonymous with poison (as mentioned previously), it simultaneously enjoys a positive reputation for certain therapeutic actions. Its virtuous medicinal effects have been touted as far back as Hippocrates (460-357 B. C.), who used it to treat ulcers

(Newman, 2005). The fact remains that arsenicals, like arsenious oxide, are effective killers. As such, they will eliminate many disease-causing organisms from the human body. For example, arsenic-based organic compounds have been developed to treat syphilis spirochetes (in fact, it was the first effective remedy for syphilis), amebae, African sleeping sickness organisms, and many other parasites (Newman, 2005; Schroeder, 1974, p. 97). In fact, a tonic known as Fowlers solutionintroduced in 1786composed of many arsenicals, but primarily arsenious oxide (the same white compound formerly known as inheritance powder), became widely popular as a prescription medicine. Further, vendors did not need to hide the fact that arsenic was a famous poison. The label on a bottle of Fowlers solution, directly states: Arsenious acid is in large doses an irritant and in small doses a tonic; and by virtue of its tonic action it possesses febrifuge and alternative properties. As an irritant it is a poison, and a very powerful one, a few grains being adequate to occasion death. (Christison and Griffith's Dispensatory, 1848) Although its toxicity was well known, it was believed to function as an external and an internal remedy in small doses (Christison and Griffith's Dispensatory, 1848). The doctors and scientists of the time believed that arsenical dose-response curves displayed hormesisthat low dose exposures often resulted in beneficial effects, even though high dose exposures caused harm (Klaunig & Kamendulis, 2010, p. 116). The logic was that it killed the malignancies that it acted uponbut it was not potent enough to kill the user. Apparently, this logic was convincing, Fowlers solution sold well for over 150 years (Christison and Griffith's Dispensatory, 1848). The reason why this type of low dose arsenic therapy is not popular today is that its long term effects have been found to be carcinogenic. Poisoning by arsenic is now relatively rare because of the tests that have been developed to detect arsenic poisoning, and thereby prosecute

poisoners (to include the Marsh and Gutzeit methods), but as a carcinogen, arsenic now poses a new public health risk (Fairhall, 1957, p. 19). The carcinogenic toxicity of small concentrations of arsenic is especially problematic in places where the ground water has been found to be contaminated with the metalloid and its derivatives. For example, much of the population of Bangladesh has been experiencing increased incidences of cancer in the last 30 to 40 years. The problem began in the 1970s and 1980s, when there was a major push by the Bangladesh government and non-governmental organizations, like UNICEF, to provide clean water access to the villagers of the country. Previously, inadequate water purification and sewage systems, and periodic flooding had been contaminating potable water sources, resulting in high infant mortality rates and widespread disease. To mitigate this problem, an initiative was undertaken to construct millions of deep tube wells in village communities to provide these communities with access presumably clean ground water. Almost 8 million deep tube wells were dug. Although the initiative succeeded in decreasing water-borne diseases, cancer incidence rates spiked because approximately one in the five of those wells is contaminated with arsenic (Chowdhury, 2004). Ironically, not only does arsenic cause cancer, but it is also used to treat cancer. Studies conducted toward the end of the twentieth century have actually shown that arsenious oxide (again, the same white compound formerly known as inheritance powder) is an effective chemotherapy for certain cancersparticularly acute promyelocytic leukemia (APL). People suffering from this disease have a mutated gene that creates a dysfunctional protein, which interferes with the normal growth and death of specific white blood cells. Arsenious oxide, marketed as Trisenox, has been approved by the U. S. Food and Drug Administration for treatment of this cancer because it effectively destroys this dysfunctional protein and allows

these white blood cells to grow normally. Arsenious oxides future as a cancer-fighting drug looks promising: Trisenox, which some doctors say is less toxic than conventional chemotherapy, shows promise in treatments of other types of cancer and is undergoing clinical trials for lymphoma, prostate, and cervical cancers (Smith, 2002). Although it may seem illogical that a carcinogen can also fight cancer, this is actually the norm. Toxicologist Mike Gallo admits: Almost all cancer drugs are carcinogenic in their own right (Newman, 2005). Therefore, since ancient times to the present day, arsenic has and continues to be a toxicological contradiction.

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