1 Arsenic Poisoning Through the Ages Jerome O. Nriagu University of Michigan, Ann Arbor, Michigan 1. INTRODUCTION Arsenic is mined from deep mines, for it is a material that Nature hides from us, teaching us to leave it alone as harmful, but this does not cause the arro- gant miners to leave it (1, p 106) Arsenic, the king of poisons, has probably influenced human history more than any other element or toxic compound. This enigmatic metal (chemically, arsenic is a metalloid but will be referred to as a metal throughout this chapter) began its long association with human culture by poisoning the god (Hephaestus) who first endeavored to find some beneficial use for it. In subsequent ages, it was used nefariously to kill many aristocratic and noble gentlemen, terrorize others, and engender events that influenced the cultural and social developments in many parts of the world. Until the recent emancipation of women, arsenic was a key instrument employed by women to free themselves from tyrannical husbands and unwanted lovers. Arsenic’s misguided benevolence was equally romanticized so that it was able to achieve widespread acclaim, becoming, at the turn of the century, the best agent in pharmacopoeia of the Western world. Millions of people probably received arsenicism rather than cure for trusting their health to arsenical preparations. The long fight with pests was tipped in humanity's favor when arsenic was brought in as pest killer. The pesticide sprays began the practice of contaminating human foods and environment with arsenic, resulting in untold effects on the health of many people and their offspring. By lurking underground, arsenic threatens the drinking water resources in many parts of the world, and the consumption of the tainted water over the years must have resulted in untold 12 Nriagu suffering by millions of people, Many scientific disciplines, such as toxicology, forensic science, and analytical chemistry, owe their origin and development to the fascination with arsenic and the need to reveal its presence in our air, drinks, and food. This chapter presents a brief overview of arsenic exposure through the ages and makes the case that arsenic has poisoned and killed more people than any toxin known to humankind. Il, ANCIENT TIMES The role of arsenic in metallurgical development at the beginning of the Bronze Age is well documented (2). In many places, arsenic minerals tend to co-occur with copper minerals, and during primitive smelting operations some of the arse- nic would have been alloyed by chance with the copper. Perceptive smiths of those days would have noticed that some copper alloys were more desirable than others and subsequently would have made some conscious effort to select miner- als that would yield the preferred copperarsenic alloys (2,3). The primitive fur- naces would have generated copious fumes of toxic, garlic-smelling arsenious oxide (As,O,), which could have adversely affected the health and life expec- tancy of the smiths (4). Exposure to the toxic arsenical fumes conceivably could have resulted in degenerative changes manifested as polyneuritis and muscular atrophy in limbs leading ultimately to lameness. The deformity of Hephaestus (or Hephaistos), the mythical Greek god of fire and technology, his Roman coun- terpart (Vulcan), and the patron gods of smiths in many other cultures might have been an occupational disease linkable to effects of exposure to toxic fumes of arsenic or lead (5,6). The change in the caricature image of Hephaestus the smith with the passage of time from the buffoonlike achondroplastic walk to the club- footed limp and eventually to normal behavior has been related to improvements in smelting techniques and the switch to widespread use of cassiterite (SnO:), which minimized the deformatory effects of occupational exposure to arsenic. Regardless as to whether the physical deformities of the patron gods of smiths were related to the unhealthiness of their craft, arsenic poisoning appears to have been among the first occupational diseases to afflict humankind. In all likelihood, arsenic poisoned the first person who managed to obtain a metallic alloy from one of its ores. The illusory similarity between anthropomorphized Hephaestus and arsenic is striking. Both had questionable fathers—**Hera gave birth to Hephaestus with- out intercourse with the other sex but according to Homer he was one of her children with Zeus’ (7, I, iii, p 5), while the origin of metallic arsenic is shrouded in mystery. Neither had alluring physical qualities Hephaestus limped about on an ill-matched pair of feeble legs, while metallic arsenic possesses few desirable physical properties and was depicted allegorically as a serpent in alchemical texts.Arsenic Poisoning Through the Ages 3 Both fell from grace—early in his life, Hephaestus was hurled down from heaven, while the use or mention of arsenic was outlawed in many cultures. Both were subsequently rehabilitated—Hephaestus was called back to Olympus where he lived in his palace and worked on his forge, while arsenic achieved fame as the backbone of Western pharmacopoeia until fairly recent times. Both felt un- wanted—Hephaestus intoned “I was born mis-shapen . . . would they [his par- ents] had never begotten me,”’ while no one could find a use for metallic arsenic for a long time. In the end, both helped to forge human history—Hephaestus taught men glorious crafts throughout the world, while human history could never have been the same without arsenic. ‘Application of arsenic in ancient metallurgy other than as arsenical bronze was limited. It was used by the Egyptians in the third millennium B.C. as well as in ancient China to produce a silvery surface on mirrors and statues (8,9). It was cited in one of the first treatises on glass as one of the fluxing ingredients, its presumed effect being to produce crystallization during the cooling of the glass (10). Arsenic fumes would have been a hazard to the people who made such artifacts. Occupational exposure to arsenic in ancient times would have extended beyond the bronze makers and their families. Many copper, gold, and lead ores contain significant amounts of arsenic. Most of the arsenic went into the smoke, which was inhaled by the artisans and contaminated the surrounding areas. Arse- nic poisoning remained a real and persistent hazard to many people involved in the smelting and recovery of copper, gold, and lead in ancient times. Workers so afflicted would have numbered in the millions. Orphiment (As,Ss, the yellow arsenic sulfide) and realgar (As,S;) were also used as depilatories in the leather industry with a high probability of exposure of ancient workers. ‘The ancients believed that orphiment contained gold, hence the name auro- pigmentum, Pyrite and arsenopyrite, often with high arsenic content, have been known as fool's gold since time immemorial. Mappae Clavicula, an eclectic com- pilation of ancient alchemical methods, listed many recipes for using orphiment to make gold, to make silver from copper, and to cover iron and tin objects with gold color (11). Pliny described the effort of emperor Caligula to extract gold from orphiment and noted that while some gold was obtained, the quantity was so small that despite the low price of orphiment, which was about four denarii per pound, the operation was deemed unprofitable. In A.D. 260, the emperor Diocletian was so disgusted with the failure of Egyptian alchemists to extract gold from orphiment that he collected all the books dealing with transmutation and had them destroyed (12). The alchemists who relied on orphiment to make gold were probably rewarded with arsenicism rather than materially for their effort. Orphiment was used in ancient times as pigment. It was found in a linen bag in King Tutankhamun’s tomb, in wall paintings of the Theban necropolis, and more extensively from the Eighteenth Dynasty onward (13). Since the mineral is4 Nriagu not found in Egypt, it must have been imported from Persia, Armenia, or Asia Minor. Orphiment and realgar were occasionally cited in the Akkadian texts as ingredients of ornamental paint and for cosmetic purposes (14). Realgar was iden- tified as the red pigment in a pot excavated at Corinth and orphiment has been identified in yellow pigments found in ancient Greek graves (15). Pliny (16, XXXII, p 79) noted that in his time there was “‘a recipe to make gold from orphiment which occurs near the surface of the earth in Syria, and is dug up by painters."” The number of ancient painters and artists who were occupationally exposed to arsenic is impossible to estimate at this time. Strabo (17, p 40) referred to a mine of yellow and red sulfides near Pompeiopolis where, because of its poisonous character, only slaves were employed. Arsenic was featured extensively in the materia medica of ancient cultures. The name arsenic itself is derived from the Greek word arsenikon, which means potent (18). Both orphiment and realgar were mentioned in the ancient medic texts of Assyria (19) and some of the so-called malachites, hematites, yellow and red ochres, and iron pyrites mentioned extensively in the Ebers Papyrus of Egypt (about 1550 B.C.) presumably consisted of arsenic sulfides (5). Hippocrates (460-377 B.C.) used orphiment and realgar as escharotics. Dioscorides (20, L, xxx and xxxi) notes that orphiment “‘is astringent and corrosive, burning the skin with severe pain and produces eschar. It removes fungal flesh and is a depila- tory.” In describing the medicinal properties of realgar, he notes that when “‘mixed with resin, it causes hair to grow when destroyed by pellagra, and that with pitch it serves to remove rough and deformed nails. With oil, it is used to destroy lice, to resolve abscesses, to heal ulcers of the nose, mouth and funda- ment. With wine, it is given for fetid expectoration and its vapor, with those of resin, are inhaled in chronic cough. With honey, it clears the voice and with resin is good for shortness of breath.” Pliny furnishes an identical description of the medicinal properties of the arsenic sulfides. Galen (A.D. 130-200) also recom- mended a paste of orphiment for treatment of ulcers. Other noted ancient medical authorities, including Aristotle, Celsus, Caelius Aurelianus, Aetius, and Soranus, all employed orphiment and realgar for various curative purposes (21). The liter- ary records thus point to the fact that in ancient cultures of the West, medicinal exposure to arsenic was widespread and was a public health hazard. Arsenic minerals were valued for their medical properties by ancient Indian cultures during the age of Buddha. The Charaka-Samhita medical texts recom- mend Ala or Haritala (orphiment) and Manahsila (realgar) for external and inter- nal medication (12). The multitude of names for arsenic compounds in Sanskrit (Sankh, and Sabala Kshara), Hindi (Sanbul-Khar, Sammal Khar, Sankhyia San- bul, and Sankyhia) and Bengali (Sanka or Senko) suggest general familiarity and extensive use of these compounds in some curative and nefarious ways (12). In the Rasa system of Indian medicine, it is claimed that orphiment (Haritalam) “cures phlegm, poison, excess air and fear from ghosts. It stops menstrual dis-Copyrighted Material Arsenic Poisoning Through the Ages 5 charge, is soothing, pungent and produces warm effect on the system. It increases appetite and cures leprosy” (22, vol 2, p 157). By contrast, improperly purified orphiment is said to shorten life, give rise to abnormal excess of air, inflammation, boils, and contraction of the limbs, and hence one is adjoined to purify it very carefully (22). Realgar (Manas-shila) is said to be an “improver of complexion, a laxative, producer of heal in the system, destroyer of fat, curer of poison, asthmst, bronchitis, impurities of the blood and evil effects of ghosts’* (22, vol 2, p 198). Unpurified realgar on the other hand ‘gives rise to stone disease, stricture, gleet, loss of appetite and constipation” (22, vol 2, p 198). The problem of arsenic poisoning became so common that a number of antidotes for both orphiment and realgar were also provided in the Ras-Jala Nidhi medieval compendium (22). Realgar (Hiung-hwang, Hwang-kin-shih, Ming-hiung or T’u-hiung) was produced from several places in ancient China (23). It is said to be spermati and masculine, and of the Yang principle, just as orphiment is female, and of the germinal or Yin principle. It was regarded as the germ of gold, and was used in soldering gold, hence one of its names, Hwang-kin-shih (23). Its antifebrile, prophylactic, emetic, expectorant, deobstruent, arthritic, antihelmintic, antidotal, and escharotie properties were noted in Pen Ts’au and earlier works (23). Similar medical properties were also ascribed to orphiment. Arsenic was one of the com- mon ingredients of metallic elixirs consumed by the ancient Chinese in their y and/or immortality. For example, Sun Ssu-Mo, the great sev- enth century A.D, alchemist and pharmacist, revealed in his Thai-Chhing A Cheng-Jen Ta Tan (The Great Elixir of the Adepts: A Thai-Chhing Scripture) that the secret recipe for gold elixir (chin tan) consisted of 8 o7 of gold, 8 07 of mercury, I Ib of realgar, and | Ib of orphiment (24). Arsenic must therefore bear some of the blame for the metallic poisoning experienced by many Chinese alchemists and their patron emperors. Even today, many traditional Chinese me- dicinals still contain high levels of arsenic and mercury (25); arsenic remains an important ingredient of many Chinese patent and herbal medicines used in the treatment of psoriasis, asthma, tuberculosis, leukemia, and other diseases (26). The role of arsenic in ancient warfare was ingenious. It was cited as an ingredient of the devilish incendiary material used by Marcus Graceus to burn the Roman naval fleet (1, p 438), Early Chinese alchemical texts recommended arsenic sulfides for making toxic smoke bombs or “holy smokes”” for mass poi- soning of soldiers—one of the earliest references to chemical warfare, Death lamps in which oil and wax impregnated with arsenic were burned to poison victims slowly presumably owe their roots to the holy smokes of ancient Chi: nese (27). Itis debatable whether arsenic was widely used as secret poison in ancient times. Theophrastus spoke of a poison that could be moderated in such a manner a8 tw have effects in two or three months or at the end of a year or two years and remarked that the more lingering the administration, the more miserable the quest for longe} Copyrighted MaterialCopyrighted Material 6 Nriagu death. Agrippina, being intent on getting rid of Claudius but not daring to dispatch him suddenly and yet wishing not to leave him sufficient time to make new regulations regarding succession to the throne, used such a poison to deprive him of his reason: and gradually consume him (28). Later, the nefarious emperor Nero. used the same poison to dispatch Britannicus who was in line (0 succeed Claudius (28). The strategy for administering the ancient poisons was thus symptomatic of the method later used by the celebrated arsenic poisoners of the Middle Ages Il. MEDIEVAL TIMES AND MIDDLE AGES Attempts to isolat ng as the effort (0 find a universal antidote for its poisonous properties in Medieval times, Geber (Jabir ibn-Haiyan), an Arabian alchemist of the eighth century, discovered white arsenic by heating orphiment (29). Avicena (980-1038) differentiated between white, yellow, and red arsenic (29), Although many people have been cited as the discoverer of meta 1280), a German Dominica plish the fe minerals was made by Biringuccio in 1540; “They also say, as | told you before, that orphiment and crystalline arsenic are not at all of the same nature. And I must say, from all that T have seen or that I think I have seen, that their composition is different. For one is clear white and citrine, and the other is of a shining and beautiful golden color” (1, p 106). He then goes on to say that when orphiment is sublimed, it makes realgar, a thing of the same nature and that ‘‘in the residue of this sublimation, or when they are roasted in some other way, they le regulus fof metallic arsenic] very white like silver but more brittle than glass” (1. p 106). Shrocder, in 1641, described a method for obtaining elemental arsenic by reducing white arsenic with charcoal (29). In 1733, Brand showed that white arsenic was a calx or oxide of elemental arsenic (31). Arsine (AsH,) was discov- ered by Scheele, the famous Swedish chemist, in 1775, but little was known of its deadly nature until Geblen, a professor of chemistry in Munich, died in 1815 by inhaling a minute quantity of the pure gas. By heating a mixture of equal weights of potassium acctate and arsenious oxide, Cadet, in 1760, obtained a heavy brown, strongly fuming liquid of fearful odor (32), Robert Wilhelm Bunsen (1811-1899) was able to isolate cacody! oxide, C,H). As2Os, to which the name cacodyl (from KakwOnG, stinking) was given by Berzelius, Although the daring experiments brought Bunsen instant acclaim, he nearly killed himself from arse- ‘tic poisoning and he also lost the sight of one eye to an explosion of the com- pound (32). The discovery and characterization of the vario. nic compounds served to bring the element into more intimate contact with human culture, Poi- sonings of Gehlen and Bunsen by arsenic were not isolated incidents; many chem- and study elemental arsenic became a rustr Hic arsenic, some people credit Albertus Magnus (1193— scholar and alchemist, with at (30). A clear distinction between element: 2 the first to aecom- I arsenic and arsenic ve a ars Copyrighted MaterialArsenic Poisoning Through the Ages 7 ists and alchemists who worked with arsenic during the same period probably paid a toll with their health. A. Uses of Arsenic Finding metallurgical uses for arsenic continued to elude the craftsmen, except as Biringuccio (1, p 105) noted: “‘they penetrate very easily into fused metals, and indeed they act in such a way that they corrupt and convert almost into another nature any metal with which they find themselves. . .. With these [orphi ment and arsenic] the fraudulent alchemists blanch copper, brass and even lead to the whiteness of silver.” Mappae Clavicula, an eleventh century compilation of medieval techniques had earlier listed 33 orphiment-containing recipes dealing with metals, pigments, and chemical operations (11). In medieval times espe- cially, orphiment was sought as an ingredient for the philosopher's touchstone, an elusive magical wand for converting base metals into gold. Until well into the seventeenth century, chemistry was a handmaid of paint- ing, which in turn was closely interwoven with medicine. Colors and other mate- tial, when not furnished by monks who retained the ancient habits of the cloister, were provided by the apothecary (33). The most valuable treatises on the arts ‘were composed by physicians, and many famous painters (such as Leonardo de Vinci) were equally noted in the medical sciences, Throughout most of this time, the principal uses for arsenic were in chemistry (homicidal and practical), paint- ing, and medicine. In its natural state, orphiment has a mica-like sparkle that recalls the luster of metallic gold, and painters then being more practical than the scientists or the alchemists, found the close resemblance to gold to be of immense benefit to their work. Orphiment was a regular ingredient for most of the compounds concocted in the Middle Ages for painting and writing in gold (34,35). Mixtures of orphi- ment with calcined bone, ground eggshells or oyster shells were used extensively as bone white and inert white where white lead was deemed inappropriate. Greens were sometimes made by mixing yellow orphiment with blue pigments. Realgar, with its beautiful orange-scarlet hue, was not common in medieval paintings al- though Cennini (36) mentioned it, though not enthusiastically. The poisoning of painters by arsenic in golden orphiment in their palate during the Middle Ages presumably was common. The toll among the painters and the people who made and/or mixed the arsenious pigments must have been high. Orphiment and realgar used in the Middle Ages were either obtained from mines or prepared artificially. Natural orphiment was obtained in masses from the neighborhood of Naples and in other volcanic countries (35), or imported from Asia Minor (1). The occupational hazard of mining orphiment was well recognized at the time: ‘*On account of its poisonous exhalation, after they have made very deep mines and have found it, they pass through it with mouth and8 Nriagu nose closed with a sponge wet with vinegar if they wish to save their lives, and they do not remove the earth around or upon that which they have found it”” (1, p 106). Unfortunately, the protective measures employed by miners were generally ignored by people who made the arseniferous products. Many polymetallic ores of copper, zinc, and lead in Europe and elsewhere were said to contain significant amounts of arsenic as an unwanted impurity—“‘experienced mineralogists say that some of this [white arsenic] is found in the company of almost all the metal ores and that itis this which consumes and carries away in the smelting operations the silver that they contain’” (1, p 106). The people might not have lost their silver to arsenic but their health and life expectancy instead. In his Pharmacologia published in 1812, John Paris, a British physician, described many cases of cancer among workers involved in the production of tin and copper and in farm animals grazing in the vicinity of copper smelters. He attributed all of these diseases to poisoning by arsenic present in ores of many metals (37). Although Paris’s speculation on the arsenic origin for the cancers is difficult to prove, his report drew attention to potential environmental and human health effects of roguish arsenic in many ores. B. Homicidal Poisoning and Arsenophobia Arsenic became practically synonymous with poison during the Middle Ages when the art of secret poisoning became part of the social and political life. Arsenic oxide, reputedly discovered by Geber, was an ideal suicidal and homi- cidal poison for the time. IL is tasteless, odorless, cheap, powdery white and hence can be administered with sugar, does not diminish appetite, is fatal in small doses, and the symptoms of chronic and acute poisoning mimic natural diseases thereby obfuscating the true cause of death. Its effects tend to be cumulative, enabling the poisoner to weaken the victim with small doses over a period of time before administering the fatal dose. One of the earliest accounts (in western Europe) of the use of arsenic for homicidal purposes was in 1314 when Charles the Bad, King of Navarre, tried unsuccessfully to use arsenic trioxide from apothecaries to murder his brother Charles VI, King of France. Karl the Evil, in 1383, noted the ready availability of arsenic all over France: ‘ou are going to Paris . . . you will find arsenic at Pampelune, Bordeaux, at Bayonne, and from every one of the pretty villages where you pass, at the apothecaries’ hospitals” (21, p 14). In the late 1600s, the infamous Tophana or Toffana of Palermo and Naples dis- tributed her murderous oil marked Manna of St. Nicholas of Bari (a sanctimo- nious appellation) as charity to wives who wished to have other husbands. It is estimated that over 600 persons perished from Aqua della Toffana, which became a generic name for secret poisons sold widely in Europe between 1630 and 1730 (28). Apocryphal vignettes of the Aqua della Toffana homicides can still be seen in John Kesselring’s (38) play, Arsenic and Old Lace, in which old ladies usedArsenic Poisoning Through the Ages 9 elderberry wine spiked with arsenic, cyanide, and strychnine to dispatch their gentlemen callers. In the court of France, there were so many notorious poisoners that the name poudre de succession (inheritance powder) for white arsenic be- came a nightmare and a destabilizing influence as the heads of the great families came to regard all relatives and friends with extreme suspicion. The punishment for the treacherous act was harsh: “If a Christian disavows faith or works magic or the mixing of poison and is caught in the act, the person shall be burned ona rack” (21, p 8). For the rich and famous and men with unhappy spouses, nevertheless, arsenic powder remained a hazard to life and property until James Marsh published his method for detecting low levels of arsenic in 1836 (37). C. Arsenic in Medicine The Arabian physicians copied and slightly modified the medical uses of arsenic described by Dioscorides. Rhazes (ca. 850-925), for instance, recommended ar- senic in asthma, lung diseases, skin diseases, ulcerations, and with unslaked lime and opium for dysentery (21). Avicena (980-1037) used arsenic for skin diseases and lung problems, and with honey and other vehicles to improve the mucous membrane. The introduction of arsenic prophylaxis into the plague literature may be attributed to Nikolaos Myrepsos of Arabia, who alluded to arsenic compounds as ‘Persian antidote’” against plague in his extensive recipe collection (39). The collected works on the materia medica of the ancient and Arabian physicians were propagated through subsequent ages in the various books of secrets or natu- ral magic, which often included liberal interpolations by the author. Typical of these books was Natural Magik by John Baptista Porta (40), which listed many complicated remedies containing arsenic that could be used against asthma, skin diseases, and head lice. Because of its high toxicity, white arsenic was first used against external diseases of sheep and horses and was only applied in the four- teenth century in the treatment of human scrofulous ulcers (41). By the middle of the sixteenth century, arsenic compounds were primarily used for external diseases in western European medical practice—as an amulet, cauterizing agent, or as a smoke. Biringuccio was an eyewitness: ‘They say that it is a remedy against the plague to carry them [arsenic com- pounds} in a little bag over the heart, that their fumes are beneficial to those who have asthma, and that they work against chronic cough or bloody spu- tum. Orphiment mixed with lye and lime shaves every hairy spot without cutting. With these materials, a very powerful corrosive for cauterizing is made (1, p 107). Paracelsus, who broke the rigid tradition of Galenic medicine, used realgar internally against cancerlike tumors (42) but more importantly gave cogency to the belief that there was a therapeutic window for toxic compounds in which