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HISTORY OF ARSENIC AS A POISON AND A MEDICINAL AGENT

Michael F. Hughes

Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA

Disclaimer: This article has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

1.1 INTRODUCTION

Arsenic is one of the most enigmatic elements known to humankind. For many centuries, arsenic has been used as an intentional human poison, for which it has generated much fear and interest. However, over this same time frame, arsenic has been used to benefit society, at least with good intentions, as a medicinal agent. The best example of this paradox is arsenic trioxide, which is also known as the white arsenic. This potent and lethal inorganic arsenical has not only been commonly used to commit homicide but also been used more recently as an effective cancer chemotherapeutic agent.

Arsenic is an insidious poison. Over the ages, arsenic came to be known as the "King of Poisons" because of its use to poison royalty [62]. Arsenic was the choice as a poison because it has no taste and could be discreetly mixed with food or drink. The symptoms of arsenic poisoning were similar to those of common diseases (e.g., cholera) in the world at a time when hygienic practices were poor and safe drinking water was not readily available. Also, there was no chemical test to indicate that someone had been exposed to arsenic until the 1700s.

Although the poisonous nature of arsenic was well known, in 2010, in the United States alone, there were over 5000 cases of arsenic pesticide poisoning and 1000 cases of arsenic nonpesticidal poisoning [8]. Three deaths were noted in the arsenic nonpesticidal cases.

Arsenic is found in inorganic and organic forms as well as different valence or oxidation states (Fig. 1.1). The oxidation states of arsenic include -III, 0, III, and V. Examples of arsenicals in these states are arsine, elemental arsenic, arsenite, and arsenate, respectively. Arsine is a colorless, odorless gas and highly toxic [54]. Exposure to arsine is primarily occupational, so it will not be discussed in this chapter. The form and valence state of the arsenical is important in its potential toxic effects. In general terms (i) inorganic arsenicals are more potent than organic arsenicals; (ii) trivalent (III) arsenicals such as arsenite are more potent than pentavalent (V) arsenicals such as arsenate; and (iii) trivalent organic arsenicals are equally or more potent than trivalent inorganic arsenicals [30].

FIGURE 1.1 Structure of common arsenicals. The ionized forms of arsenous acid and arsenic acid are arsenite and arsenate, respectively. Dimethylarsinic acid is also named cacodylic acid.

The clinical signs of acute oral arsenic toxicity are progressive and depend on the form, valence, and dose of the arsenical. In a human adult, the lethal range of inorganic arsenic is estimated at 1-3?mg As/kg [18]. The symptoms of acute arsenic poisoning are listed in Table 1.1 [25, 56]. Diarrhea is due to increased permeability of the blood vessels. Depending on the type and amount of arsenic consumed, death may occur within 24?h to 4 days. Death is usually due to massive fluid loss leading to dehydration, decreased blood volume, and circulatory collapse. Survivors of acute arsenic poisoning may develop peripheral neuropathy, which is displayed as severe ascending weakness. This effect may last for several years. Encephalopathy may also develop, potentially from the hemorrhage that can occur from the arsenic exposure. Treatment for acute arsenic poisoning includes gastric lavage, administration of fluids and a chelator such as dimercaptopropanol, and hemodialysis.

TABLE 1.1 Acute and Chronic Clinical Effects of Inorganic Arsenic Exposure

In chronic arsenic poisoning, as in acute poisoning, essentially all the organs are affected [25, 56] (Table 1.1). The hallmark of chronic arsenic poisoning is the development of skin lesions. This includes hyper- or hypopigmentation and hyperkeratosis, particularly on the palms of the hands and soles of the feet. There is no known treatment for chronic arsenic poisoning that is of benefit to the individual. The best option is to minimize exposure to the source of arsenic and provide supportive care to the patient.

Arsenic is also a known human carcinogen, being classified as such by the International Agency for Research on Cancer [33] and the US Environmental Protection Agency (USEPA) [39]. Confirmed organs for cancerous development from chronic arsenic exposure include bladder, skin, and lung [51]. Potential target organs for cancer from arsenic exposure are liver, kidney, and prostate [33, 51].

1.2 INTENTIONAL POISONING BY ARSENIC

The poisonous nature of arsenic has been known for centuries, and thus, it has been used to commit homicide. It is so well known that poisoning by arsenic has been incorporated into the plots of literary works of Chaucer, Agatha Christie, and other writers, and even in the title of a 1940s Broadway play, "Arsenic and Old Lace" [6]. However, it is inconceivable that the victims would die so quickly from arsenic ingestion in that play. Their deaths would most likely be from the ingestion of cyanide and strychnine, which were also part of the poisonous concoction mixed with elderberry wine. But would the play have gained as much attention if it had been called "Cyanide, Strychnine and Old Lace"? No one knows for sure.

There have been many suspicious poisonings, potentially by arsenic, of powerful people in centuries long ago. It has been suggested that Alexander the Great and Britanicus were poisoned by arsenic [6, 12, 25]. The Greek physician Dioscorides, in the first century a.d., included arsenic as a poison in his five-volume publication De Materia Medica ("Regarding Medical Materials") [48]. During the Middle Ages and Renaissance periods, murder by poisoning reached its zenith [6, 12]. Noted individuals who poisoned others with arsenic for personal gain or profit during this time include the Italians Cesare Borgia, Giulia Toffana, and Hieronyma Spara, and the French woman Marie de Brinvillers [6, 12]. Some of the poisonings were politically motivated, particularly in the Catholic Church, as several senior clergymen were poisoned with arsenic over a 500-year period [12, 48].

An interesting and curious case of arsenic poisoning involved several elderly women of the village of Nagyrev in south-central Hungary [27]. In 1929, four women were brought to trial accused of murdering family members. Their basic plan was to call a doctor to the home of the intended victim. Many of the victims were chronically ill with tuberculosis or another debilitating disease. After the doctor departed, the victims were poisoned with arsenic. When the victims passed away, questions were not asked, because it was perceived that they died from complications of the noted illness. During this time, arsenic was easily available as arsenic acid as this agent was used as a rodenticide. Also, flypaper containing arsenic was commonly used. The arsenic was easily extracted from the flypaper and could be mixed with a drink, as one of the accused allegedly did with her husband's apricot brandy. There were other suspicious deaths at this time in this village, so 50 bodies from the town's cemetery were exhumed. Forty-six of the deceased had arsenic levels high enough to be lethal. Other women were brought to trial later and charged with the murders of husbands, fathers, sons, and mothers- and fathers-in-law. Several of the women were found guilty of murder and punished, while others were acquitted of the charges. It was alleged that the period of the murders in this village lasted over two decades and perhaps was even longer. It should be noted that even today, arsenic-containing...