the Duplicitous Nature of Inorganic Arsenic

A Mystery in Rome

The ambassador liked to sip her morning coffee in her bed-chamber. Perhaps, in these moments of quiet, she reviewed her career, now at its peak. She had good cause for satisfaction. Successful as a playwright, editor, and foreign correspondent; married to a magazine publishing mogul; a former United States representative; a rapier-tongued spokesperson for the Republican Party: Claire Booth Luce had been appointed in 1953 by President Eisenhower as ambassador to Italy. This posting was not a ceremonial sinecure, given the Cold War and the strength of the Communist Party in Italy at that time. However, Mrs. Luce was carrying out her diplomatic duties with characteristic vigor.

The grand, high-ceilinged bedroom typified the best in the architecture of Rome. Regrettably, the painted ceiling seemed to be shedding its plaster. Every day or so the flat surfaces of the furniture accumulated a thin layer of dust. Also, the coffee had a somewhat bitter, metallic taste. Attributing this to the poor quality of coffee available in post-war Italy, the ambassador had her favorite brand of coffee flown in from the States. Somehow, however, this didn’t taste much better.

As time went on, the ambassador’s satisfaction in her post was marred by illness. Her symptoms became noticeable in 1954: brittle fingernails, hair loss, loose teeth, anemia, and numbness in her right foot. After struggling with this mysterious illness until 1956, Mrs. Luce was forced to resign. Subsequent investigation determined that she had been suffering from chronic arsenic poisoning; the first three symptoms were deemed due to arsenic, and the last two to concomitant lead toxicity. The source of the poison was lead arsenate dust from the paint on her bedroom ceiling, ingested in her coffee and by breathing in the dust. Mrs. Luce’s health recovered after her return to the United States, and she lived until 1987 (1, 2).

This remarkable episode is the most recent illustration of the insidious way arsenic can exert its toxic effects. Arsenic’s long history of deliberate use as a homicidal poison is outside the scope of this article, but the following are some further examples of its accidental ill effects.

Arsenic in Wallpaper

Arsenic poisoning was a problem in Victorian-era England. Mainly, though not exclusively, in the form of dyes and pigments, arsenic was an ingredient of dozens of consumer products, including wallpaper, toys, food wrappers, and clothing made from dyed fabric (e.g., muslin ball gowns). The medical profession began to question the use of arsenic compounds in consumer goods as early as 1837, but more widespread concern dates from the 1850s when two doctors, Hinds and Halley, reported that they personally had experienced toxic symptoms from sitting in their green-wallpapered studies. From the early 19th century on, the color of copper arsenite (as in Scheele’s Green or emerald green) was highly favored in England. It was a popular pigment for wallpapers; in 1871 the British Medical Journal stated that a majority of dwellings, from palaces to huts, had arsenic in their wallpaper (3).

Despite reports of poisonings, there were medical men and others who defended these wallpapers. They said that copper arsenite could not volatilize, and thus could not become airborne. One prominent person on this side of the argument was the minor poet William Morris, self-styled as the “idle singer of an empty day.” Morris, better known for his contributions to the British Arts and Crafts movement, founded a design firm which sold, among other things, arsenic-containing wallpapers. In recently cited correspondence (4), dated 1885, to a customer named Nicholson, Morris pooh-poohed Mr. Nicholson’s claim that he had been poisoned by wallpaper. Morris dismissed the concerns of the medical profession and the press, saying, “the doctors were being bitten by witch fever.”

It is true that copper arsenite is non-volatile, but research done in the 1890s showed that, under humid conditions, molds (e.g., Penicillium brevicaule) living on wallpaper paste converted the arsenic salt into gaseous di- and tri-methyl arsines. Prolonged inhalation of these compounds was reputed to have caused chronic poisoning, even fatalities (1).

Because the poisoning reports were anecdotal and robust morbidity and mortality data were lacking, the British government did not intervene. In time, elimination of the use of Scheele’s Green and other forms of arsenic was brought about by the combined power of the press, the market place, and the preferences of women shopping for their families (3).

The Fatal Glass of Beer

Now arsenic was no longer put into consumer goods. Still, arsenic poisoning hit England again and again in more fully documented tragedies. In 1900–1901, at least seventy people in Manchester, Salford, and surrounding areas were fatally poisoned by arsenic contained in their beer. Investigation revealed that there was arsenic in two sugars used in the brewing process: glucose, derived from starch hydrolysis, used in the mash; and invert sugar, from cane sugar, used in priming. Tracing further back, it was found that the sulfuric acid used in hydrolyzing the starch and cane sugar had a high arsenic content (5).

Another outbreak of arsenic poisoning among beer drinkers occurred in Halifax, in the North of England, in 1902. Two people died, and the source of the arsenic was found to be the gas coke used for drying the malt (5). Finally, a Royal Commission on Arsenic Poisoning was formed, and preventive measures were instituted which put an end to beer poisonings (5).

Environmental Arsenic Poisoning

The numbers of victims in the above-described events are dwarfed by the millions who are subject to arsenic in the environment in our own day. Few are aware that arsenic is the twentieth most abundant element in the earth’s crust (6). It occurs in a number of minerals and finds its way into groundwater, the main source of drinking water in many countries. In this way many millions of people are exposed to arsenic, most notably in Bangladesh, India, and China (6). Arsenic poisoning occurring in Bangladesh has been called the largest mass poisoning of a population in history. It is also an example of the unanticipated consequences of a good deed. Bangladeshis drinking contaminated river water frequently contracted cholera and other bacteria-borne diarrheal diseases. Wishing to provide a safer source of water, international aid organizations, beginning in the 1970s, assisted in digging millions of wells throughout the country. To make this project affordable, they dug relatively shallow wells known as tube wells, which cost only one-tenth as much to dig as deep wells. Much of the groundwater tapped by the tube wells, however, contains high levels of arsenic, as well as several other toxic metals.

By 1993, the government of Bangladesh was reporting wide-spread signs of arsenic poisoning among the population, traceable to tube well water. A 1997 study of 570 tube wells by the United States Agency for International Development (USAID) found that wells in about 45% of Bangladesh have arsenic concentrations above fifty parts per billion (ppb), whereas the World Health Organization (WHO) advocates ten ppb as a safe maximum (7). Efforts are underway to provide safe drinking water in Bangladesh, but given the country’s pervasive poverty, the massive extent of the problem, and the need to rely largely on outside help, it is certain that people will continue to be exposed for a long time.

Even in the United States there are communities whose water contains excessive arsenic. For example, in New Mexico half a million people are thought to be affected (7). The current Environmental Protection Agency (EPA) limit for arsenic in drinking water is fifty ppb; in 2006, it is due to drop to the WHO standard of ten ppb. This is a matter of controversy because of the expense involved in mitigating the arsenic levels. In 2001, EPA administrator Christie Whitman withdrew release of the ten ppb standard, but was later forced to reinstate it by public and Congressional protests (8, 9).

Effects of Arsenic Toxicity

In view of all this disconcerting information, the reader may want to know how arsenic poisoning manifests itself. The effects of arsenic toxicity have been summarized as follows (10).

Acute arsenic toxicity:

• gastrointestinal symptoms: abdominal pain, vomiting, diarrhea, and hemorrhagic gastroenteritis arising from transmural mucosal inflammation that may be accompanied by hepatic necrosis.

• vascular endothelial injury: capillary leak, pulmonary edema, hypotension, shock; this may lead to renal failure and acute respiratory distress syndrome (ARDS).

• progressive neuropathy similar to Guillain-Barre syndrome.

• cardiac dysrhythmias: torsade des pointes, ventricular fibrillation, and sudden death.

Chronic arsenic toxicity:

• changes in skin and adnexa (i.e., appendages), deposition in the dermis which may be diffuse or appear flecked, keratoses of palms and soles, and lines in the nail beds.

• less common: gangrene of the legs and feet (e.g., black-foot disease) resulting from chronic vasospasm.

Arsenic as Medicine

Few things in this world are completely evil, and arsenic has also been harnessed for medicinal use. Roughly a century ago, arsenic formed the structural centerpiece of arsphenamine. Known as Salvarsan or Compound 606, this molecule was the first wonder drug: the cure for syphilis. Arsphenamine was soon followed by neoarsphenamine, which was water-soluble and easier to administer. The exciting story of the discovery of these compounds by Paul Ehrlich has been summarized by Sneader (11). These drugs were the mainstay of syphilis chemotherapy for forty years, until the advent of penicillin rendered them obsolete.

In the realm of inorganic arsenic—the focus of this article—the most prominent medicinal compound is arsenic trioxide (As₂O₃), solubilized as the arsenite salt of an alkali metal. Two such products will be discussed in greater detail: Fowler’s Solution, which faded away after some 150 years of use, and its recent reincarnation, Trisenox^®.

Fowler’s Solution

Although arsenic had been used in medicine since ancient times, its modern history starts in late18^th century England. In 1771, Thomas Wilson of London marketed a secret formula called “Tasteless Ague and Fever Drops.” One of the medical practitioners who used these drops with good results was Thomas Fowler, at the infirmary of Stafford. Fowler asked the infirmary apothecary, Mr. Hughes, to analyze Wilson’s drops and try to duplicate them. Hughes’s work resulted in a solution of potassium arsenite, made by boiling As₂O₃ with potassium bicarbonate (KHCO₃). (Hughes probably did not understand the nature of the chemical reaction, given the state of chemical knowledge in the 1770s.) Fowler named his product “Liquor Mineralis.”

Fowler carried out a study on the treatment of malaria with his solution, and published a “Medical Report of the Effects of Arsenic in Cases of Agues, Remittent Fevers, and Periodical Headaches” in 1786. The medical profession enthusiastically received his work, and Liquor Mineralis became widely known as Fowler’s Solution. It was accepted into the London Pharmacopeia of 1809, and into the first United States Pharmacopeia, issued in 1820 (10, 12).

Throughout the 19^th century Fowler’s Solution was deemed a useful alternative to quinine for malaria, and there were also claims of beneficial effects in syphilis. In 1858, David Livingstone, the medical missionary of “Stanley and Livingstone” fame, recommended Fowler’s Solution for sleeping sickness (10). Arsenic’s anti-treponemal and anti-trypanosomal effects were thus foreshadowed prior to Ehrlich’s discoveries.

The use of Fowler’s Solution persisted until about 1940, though on a more nonspecific basis. Small doses were administered as a “tonic” to malnourished or convalescent patients. Early effects of chronic toxicity (e.g., capillary fragility) caused flushing of the cheeks, making the patient look healthier (13). Fowler’s Solution was said to be an “alterative,” a therapeutic category vaguely defined as “drugs whose mode of action is unknown, but which improve the nutrition of the tissues and help to absorb diseased tissues, thereby restoring them to their normal condition.” The source of this definition, a 1926 textbook, goes on to say “They are not very effective remedies and are gradually falling into disuse” (14).

Though no longer considered a useful antimalarial, antisyphilitic, or general tonic, Fowler’s Solution was sporadically tried for the treatment of leukemia. At a 1940 therapy conference, Forkner cited reports from 1865 and 1878 (15). Forkner described a dosage regimen for Fowler’s Solution that he found comparable to X-ray or radium for inducing remission in chronic myelogenous leukemia (CML). After ten to twelve days of treatment, he reported, the leukocyte count drops sharply, anemia is lessened, and remission becomes apparent. Most of the arsenic side effects were tolerable, but on rare occasions, the development of peripheral neuritis in his treated patients forced him to discontinue treatment.

Why was there no intensive follow- up of this approach, at a time when the diagnosis of leukemia was a sure death sentence? Perhaps it was because World War II drew medical research into other areas. The post-War period saw the introduction of the nitrogen mustards, followed by the anti-metabolites, and the entire current armamentarium of cancer chemotherapy.

Trisenox^®

Nevertheless, arsenic was not wholly forgotten. In the early 1970s, some Chinese physicians, analyzing a number of traditional preparations used in treating cancer, found As₂O₃ to be a common component of these products. They proceeded to test the compound in a variety of cancers, and obtained remission rates of 90% in relapsed acute promyelocytic leukemia (APL). Favorable results in APL were also reported in other studies in Europe and North America (10).

Armed with the knowledge that As₂O₃ was the active ingredient, the company Cell Therapeutics developed Trisenox^® and brought it through the Food and Drug Administration (FDA) review and approval process. Trisenox^® received FDA approval on September 25, 2000 for treatment of relapsed APL.

What is APL? The myeloid leukemias are classified on the basis of the morphology and granularity of the abnormal cells. Normally, bone marrow cells called myeloblasts develop into myelocytes, large cells from which leukocytes are derived (16). The promyelocyte, a large mononuclear cell, is an intermediate stage in this development process. In APL, differentiation is blocked at the promyelocyte stage and promyelocytes accumulate. Clinically, the disease often presents with disseminated intravascular coagulation (10).

Approximately 20 to 30% of patients either do not achieve remission or undergo relapse after remission after treatment with the current first-line therapy for APL—an anthracycline plus oral all trans-retinoic acid (ATRA). Trisenox^® is intended for use in these patients.

APL is a rare malignancy; there are 1200 to 1500 new cases a year in the United States. Trisenox^® was therefore granted orphan drug status, giving its sponsor a seven-year period of exclusivity. The patient database on which the product was approved comprised only forty patients. Twentyeight (70%) of these patients achieved complete remission, and six others were deemed possible responders. A historical cohort of twenty-seven patients treated with ATRA had only a 22% response rate (10).

Fowler’s Solution and Trisenox® are compared below, showing that, despite significant differences, the newer product may be considered a “reincarnation” of the older.

Subsequent FDA approval of As₂O₃ for APL and the above-cited literature on its effects in CML (15) make it likely that further research on anticancer activity of arsenic will be stimulated. Indeed, this is already occurring. A recent review on multiple myeloma (MM) mentions preliminary clinical results, which suggest that As₂O₃ has activity against MM. Trials are said to be in progress to confirm activity and determine optimal dosing (17). One might speculate that had As₂O₃ been synthesized as part of a cancer chemotherapy screening-program it would be thought of as a cytotoxic agent having serious side effects, as do all cytotoxic agents. It is probably not more poisonous than most of the anticancer agents now in use.

From antiquity to the present, the history of arsenic is double-edged—comprising a poisonous edge and a medicinal edge. A few episodes from arsenic’s rich history have been discussed here. It is to be hoped that accidental arsenic poisoning, whether from wallpaper, beer, or embassy ceilings, is a thing of the past. Equally, it is hoped that the near future will bring a solution to the problem of environmental poisoning. Finally, clinical trials carried out under modern protocols should clarify what role arsenic may play in the fight against cancer.

Carcinogenicity

The medical community has recently been reminded of the carcinogenic and cocarcinogenic effects of arsenic. It has been documented that long-term exposure to inorganic arsenic increases the risk of cancer, primarily of the skin and lungs. Further, a recently completed study conducted in Taiwan found a synergistic relationship between cigarette smoking and ingested arsenic on the risk of lung cancer (18, 19).