Arsenic: Not So Evil After All? - Journal of Chemical Education (ACS

This article presents parts of the history of the element arsenic in order to illustrate processes behind development of knowledge in chemistry. The p...
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Chemistry for Everyone

Arsenic: Not So Evil After All? Annette Lykknes* and Lise Kvittingen** Department of Chemistry, Norwegian University of Science and Technology, 7491 Trondheim, Norway; *[email protected]; **[email protected]

Teaching concepts, models, laws, facts, and mathematical relations to our students in order to provide basic chemical knowledge for their work and life are accepted prerequisites; however, most teachers will agree that these are not sufficient. Many teachers would like to present more of the “identity of chemistry” even though we might have problems to define this neatly and clearly. Part of this identity, however, is to understand that chemistry has been and, indeed, still is a developing process, rather than a set of clearcut final products as presented in most textbooks—a fate shared by other sciences. The periodic table and the individual elements are major points of reference in chemistry. We have therefore chosen an element, arsenic, to illustrate the processes behind development of knowledge in chemistry. Furthermore because many of us associate arsenic, known as “the king of poisons” (1), with something evil, we have purposely presented several examples of the medical uses of arsenic. Why is arsenic considered evil? According to Frost (2, 3), this is due to several cases where arsenic has been erroneously associated with poisoning, for example in Manchester in 1900, where six thousand beer consumers fell sick and seventy died (4). This scandal was blamed on arsenic-contaminated sulfuric acid used in the production of malt liquor; however, there were also deadly amounts of selenium in the beer (2). This scandal, together with the play “Arsenic and Old Lace” by Kesselring, contribute to what is called “the arsenic myth” (2, 3). The title of the play suggests arsenic as the major poison in the fatal mixture, although both the symptoms of the victims and the recipe referred to suggest something else, namely cyanide and strychnine. Arsenic as a Human Medicine: Early Years Quite counter-intuitive to the present common view of the element, arsenic compounds have been widely used as therapeutics. In 2000 B.C.E. arsenic trioxide, As2O3, obtained from copper smelting was probably used both as a drug and a poison in India and the Far East (5, 6). Later, 400 B.C.E., the Greeks became familiar with arsenic compounds, and Hippocrates and Aristotle administered orpiment (As2S3) and realgar (AsS) as escharotics and as remedies for ulcers. Some centuries later Dioscorides referred to realgar as a depilatory (7) and during the Middle Ages arsenicals were used increasingly. Paracelsus, among others, prescribed arsenic together with mercury against a number of diseases. Until the breakthrough of Fowler’s solution in the late 1700s arsenic compounds alone or in combination with other substances (such as mercury, gold, or simply the ashes of a burnt shoe sole or dragon’s blood!) were employed in the treatment of cancer, venereal diseases, nutritional disturbances, rheumatism, asthma, tuberculosis, skin disorders, and diabetes, and as sudorifics, antiseptics, cholagogues, sedatives, and tonics (8). Both external and internal use of arsenicals appeared during the eighteenth century. In this period about sixty dif-

ferent preparations were tried therapeutically and twenty or more were still common by the end of the nineteenth century. These preparations included Aiken’s Tonic Pills, Andrew’s Tonic, Arsenauro, De Valagin’s mineral solution (arsenious acid in dilute hydrochloric acid), and Donovans’s solution (iodide of arsenic and mercury) (7). Several of these drugs were still in use in the first decades of the twentieth century. Arsenic has thus proved to be one of the mainstays of the nineteenth century materia medica. Perry gives a description and usage of the various arsenic drugs. His favorite is the strychnine arsenate (9): It is what I call my therapeutic mule—it does the hardest kind of work under the most adverse conditions, with the least amount of exertion, and produces the results. As a tonic, hematinic, alterative, antiperiodic and antituberculous remedy it has a few that equals and none that excel. For years I have been using it in all forms of chronic disease, with an almost indiscriminate routineness and I have as yet no cause for regrets.

Fowler’s Solution: A Breakthrough Early in the eighteenth century arsenious acid, H3AsO3, was rendered more water-soluble when boiled with an alkali.1 This marked a milestone in the internal administration of the drug and new solutions were thus introduced. Thomas Fowler was interested in the “Tasteless Ague Drops” that were prescribed at the Stafford hospital. Together with a pharmacist he tried to copy the formula and produced a solution that became very popular and was later named after him. Fowler’s solution consisted of 1% potassium arsenite, KAsO2, from arsenic trioxide and potassium carbonate, together with some lavender to avoid confusing the drug with water. The remedy was introduced in the London Pharmacopoeia in 1809 (5, 7). It was applied as an antiperiodic and to heal asthma, syphilis, rheumatism, and skin disorders as well as being the first chemotherapeutic drug against leukemia (10). For more than a century arsenicals enjoyed popularity, but by the 1950s, after several incidences of cancer and skin disorders, the solution was withdrawn from the U.S. market (8). Arsenic trioxide is however still in use in the treatment of cancer. The Arsenic Eaters of Styria From the middle of the nineteenth century, while experts searched for an effective arsenic drug, peasants of Styria in Austria were eating small amounts of arsenic regularly. According to the legend the drug was consumed as a tonic and stimulant, a prophylactic against both diseases (11) and poisonous effects (7). Men claimed that arsenic stimulated digestion and a sexual desire, excited muscular and nervous functions, and even facilitated respiration. Women consumed arsenic to obtain a “fresh and healthy aspect” apparently by gaining weight, as well as a blooming rosy-cheeked complexion (7). The weight gain might be explained by arsenic inhibition of oxidation processes in the cells, leading to

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accumulation of fat (12),2 or to the development of dropsy (6). The rosy cheeks might be attributed to vasodilatation, another effect of arsenic. The Styrian peasants obtained the drug, hedri, hedrich, huttegruuch or hüttereich, from wandering herbalists and peddlers who had acquired it from workmen in Hungarian glass-houses, charlatans, et cetera (13). The drug was white, yellow, or gray corresponding, respectively, to arsenic trioxide, orpiment, or elementary metallic arsenic. Most arsenicophagites started their (ab)use with half a grain (0.032 g) of arsenic daily, followed by fasting, and then increasing the doses. A peasant, by account, ate four grains (0.26 g) several times a week after forty years of abuse (13) and another consumed six grains (0.39 g) daily, corresponding to three times the lethal dose (11)! Since the story of the arsenic-eating peasants began to spread, the reliability of the story has been questioned. In 1856, Kesteven, a London surgeon, tried to stem the legend by showing that all the “facts” were based exclusively on Tschudi’s work.3 In the Association Medical Journal he repeatedly stated that there was no proof of which substance the peasants actually ate (14). Maclagan (11) was nevertheless convinced that the Styrian inhabitants consumed arsenic, as he had examined their drugs, watched the peasants eating it, and found traces of arsenic in their urine. Neither was there consensus with respect to tolerance to the drug. Cloetta (15) concludes that animals can develop immunity, though, not surprisingly, only up to a certain point. Tolerance adaptation is known to exist both in microorganisms, experimental animals, and humans (16). This fact is exploited in several crime novels, for example, Strong Poison, by Dorothy Sayers, where the murderer survives a fatal meal as a result of his immunity to arsenic. Systematic Development of Arsenical Drugs Arsenic compounds have been widely used as therapeutics since antiquity. In the eighteenth and nineteenth centuries the drug was employed for almost any disease or worry. By the end of the nineteenth century, however, a systematic and scientific search for arsenic drugs emerged. In this process the Polish medical doctor Paul Ehrlich (1854–1915) was pivotal. As a result of Ehrlich and his colleagues’ investigations, a recipe for the treatment of syphilis and yaws was developed, although their original motivation lay in developments for the dye industry. As a medical student Ehrlich studied bacteria and various dyeing techniques with his cousin, Carl Weigert (1845– 1904), who used these techniques to study infected tissue. He also found selective dyeing systems that differentiated the various structures in the cell (17). Ehrlich was particularly interested in methylene blue (Figure 1), a dye synthesized in 1876 by Adolph von Baeyer and Heinrich Caro. Ehrlich discovered the specific affinity between methylene blue and nerve fibers and characterized the dye as neurotropic in 1855. Three years later he discovered that methylene blue acted as an analgesic. After realizing that methylene blue also selectively dyed malaria parasites in blood in 1890, he tested the compound on patients, who recovered from the disease. Methylene blue was thus the first synthetic drug used against a specific disease.

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The Magic Bullet Inspired by his results, Ehrlich developed a theory to explain the bonding of toxins to receptors in the cell. His quest was a drug that attacks bacteria (cells) and not human or animal tissue—“the magic bullet”. Initially he and his collaborators looked for a magic bullet among the dyes and found trypan red (Figure 2), which cured animals with sleeping sickness caused by the protozoa Trypanosoma brucei gambiense. Soon Ehrlich realized that the azo group (⫺N⫽N⫺) of the dye was the key to the effect (18) and therefore started to look for similar compounds. Owing to arsenic’s place below nitrogen in the periodic table, its derivatives were soon investigated. The first arsenic compounds (atoxyl, arsacetin, and arsenophenylglycine) proved effective on mice inoculated with the sleeping sickness protozoa. There were, however, adverse effects on the mouse nervous system and, far worse, on patients in Africa who became blind. The need for less toxic derivatives was obvious and knowledge in chemistry thus became critical. In 1905 the zoologist Fritz Schaudinn discovered Spirochaeta pallidum, the organism that causes syphilis. Schaudinn suspected a relationship to the trypanosomes, and since arsacetin was effective in animals infected with sleeping sickness, testing arsacetin in the treatment of syphilis was of interest. Both arsacetin and arsenophenylglycine cured syphilis, although there were still side effects. Ehrlich and his assistant, Sahashiro Hata, therefore started to test known dyes and arsenobenzenes against trypanosomes and spirochetes. Finally compound-606, arsphenamine (Figures 3 and 4), was found to cure both chicken spirillosis and relapsing fever. When compound-606 was also found to heal rabbits infected with syphilis, they named the compound “salvarsan”, from the Latin word salvus, meaning alive and well (19). Some side effects were still present, in particular symptoms common in arsenic poisoning, including gastrointestinal problems, anemia, neurological symptoms, and vascular reactions (19). When the water-soluble compound neoarsphenamine, compound-914 (Figure 3), was introduced, it was well received as it was easier to administer and furthermore proved less toxic than its predecessors. Despite the persistence of complaints, salvarsan and neosalvarsan became extremely popular and were the most common drugs in the treatment of syphilis until penicillin appeared in the 1950s. These compounds are no longer in therapeutic use; however, the search for the magic bullet paved the way for new scientific methods in the drug industry. Other chemotherapeutic agents also appeared as a result of the thorough work of Ehrlich and his colleagues (20). Koch writes: No medicinal preparation had ever been so thoroughly studied as salvarsan. Because of it, syphilis became better understood and the medical treatment of this scourge became more fundamental than before. The success of salvarsan was one of the great events in medical history, and following in Ehrlich’s footsteps, other valuable chemotherapeutic agents appeared....The fact that salvarsan and its derivatives have now been displaced by antibiotics and sulfa drugs takes nothing away from their usefulness and merit at the time they were in use.

Journal of Chemical Education • Vol. 80 No. 5 May 2003 • JChemEd.chem.wisc.edu

Chemistry for Everyone

The era of arsenic drugs showed the importance of logical thinking, teamwork, planning of procedure, and evaluation in drug development, which all are time consuming. The arsenic drugs were neither blind alleys in terms of drug efficiency nor with respect to scientific knowledge produced during these years of research (21).

Cl





(CH3)2N

N(CH3)2

S

N

Figure 1. Methylene blue.

H2N

R

SO3Na

NH2 NaO3S

N

N

N

N

SO3Na SO3Na

Figure 2. Trypan red.

The Use of Arsenic Drugs Today Even today arsenic compounds are in therapeutic use. Most important is melarsoprol (Figure 5), introduced clinically in 1949 as a less toxic alternative to melarsen and melarsen oxide in the treatment of sleeping sickness from Trypanosoma brucei rhodense and Trypanosoma brucei gambiense (24). The potassium derivative of the compound is more water soluble, thus allowing intramuscular and subcutaneous administration. It is, however, more toxic and less effective than melarsoprol. According to König et al. (25), melarsoprol may also cure patients suffering from chronic lymphocytic leukemia. Fowler’s solution, as mentioned, was used against leukemia in the nineteenth century, and as early as the 1960s inorganic arsenite, AsO33᎑, was applied against chronic myeloid leukemia (26). In the 1970s arsenic trioxide was found to be the effective component of an anticancer remedy. This compound has been applied in the treatment of acute promyelocyte leukemia (which accounts for 10% of all acute myeloid leukemias), chronic myeloid leukemia, and some cases of lymphoma or esophageal cancer. Derivatives of arsonic acid, RAs(O)(OH)2, were until the 1980s given to animals, as growth stimulants and in the control of intestinal diseases.4 Other arsenic compounds have been utilized as spirocheticides in poultry and to remove canine intestinal worms. Arsenocholine, a choline analogue, (CH3)3AsCH2CH2OH]+OH᎑, stimulates growth in chickens although the mechanism is still unknown (22). Arsenic: An Essential Mineral?

As

As

As

As

. 2HCl

. HCl

NH2

H2N OH

NHCH2OSO3Na

H2N

OH

OH

OH

Figure 3. Arsphenamine, compound-606 (left), and neoarsphenamine, compound-914 (right), the way Ehrlich imagined them.

( As )

n



NH3 Cl



OH

Figure 4. Today’s version of arsphenamine, based on arsenic– arsenic bond investigations and molecular weight determinations (22, 23).

CH2OH S NH2

NH

N

As S

N

N NH2

Figure 5. Melarsoprol.

A mineral is considered essential if health and growth improve on addition of sufficient amounts of the substance, deficiency symptoms appear with removal of adequate (but not toxic) amounts of the substance from the diet, and a low intake can be correlated to subnormal levels of the substance in blood or other tissues (27). In addition, the metabolic function of the substance should be known (22). On this basis arsenic is postulated to be an essential mineral. One problem in the early work on arsenic as an essential mineral was that arsenic might be a micronutrient (that is, present in amounts of less than 50 ppm), causing problems in testing for deficiency symptoms (22). Signs of reduced growth and fertility have been observed in animal diets with less than 50 ppb of arsenic. Investigations of arsenic as an essential mineral are further hampered by possible interdependence with other nutrients. Arsenic (as sodium arsenate, Na2HAsO4) in combination with zinc and arginine may influence the nutrient condition in animals (22, 28). Arsenic has thus been postulated to participate in the amino acid– protein metabolism by altering the arginine metabolism. Studies on animals indicate that arsenic is an essential mineral. A metabolic pathway in which arsenic partakes has not yet been found, however. The addition of arsenic compounds to animal feed yielding good results supports the postulate of arsenic as an essential mineral (22). Arsenic: A Dualistic Element? Most people believe arsenic is a poisonous element as its criminal use, in various forms, is well known. Arsenic compounds have been used malevolently since the sulfides

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were obtained in antiquity; however, even then orpiment and realgar were used as remedies. In the Middle Ages and the Renaissance this dual use continued; poison murderers such as the Borgia family and La Tofanya in Italy, Katarina de Medici and the marquise of Brinvilliers in France used arsenic with cruel intentions, while Paracelsus prescribed arsenic together with mercury against various diseases. During the eighteenth and nineteenth centuries arsenic compounds became even more popular as remedies, in particular the use of Fowler’s solution. In the nineteenth century Marie Lafarge in France became famous as an arsenic murderer, while Hutchinson (in 1888) postulated a relation between arsenic exposure and cancer (29), and in the same period the Styrian peasants were known to eat arsenic compounds as tonics. The duality of arsenic was thus still well established. This paradoxical pattern continued in the next century when unintended exposure to arsenic from industry resulted in serious poisoning. Criminal use of the compounds still occurred, but also legitimate use through the administration of salvarsan in the treatment of syphilis until the 1940s. Finally, today we use melarsoprol and arsenic trioxide against sleeping sickness and some forms of cancer, respectively. The effects of arsenic compounds are not easily explained. However this also applies to most chemical elements. Already in the sixteenth century Paracelsus formulated this idea as: “All substances are poisonous; there is none which is not a poison. The right dose differentiates a poison and a remedy” (8). With arsenicals, the key to the dual properties observed in connection with, for example, the treatment of syphilis, is the selective path of the drug; it is more harmful against bacteria than to humans. Conclusion The known history of arsenicals started with arsenic trioxide in about 2000 B.C.E. and today the same compound is in use against certain forms of cancer. However the mechanism of action is not yet understood. This illustrates an important aspect of chemistry in relation to humans: the elements behave in complex ways, making clear-cut and simple judgment difficult. This is both a troublesome and fascinating aspect of chemistry and our students should be presented this feature, in addition to basic chemical knowledge, in order to develop a more complete picture of chemistry as a science in process. Acknowledgments We are grateful to Reidar Stølevik, Jorunn Undheim Brænden, and Richard Verley for chemical, pharmaceutical, and linguistic advice, respectively. Notes 1. Solubility of arsenious acid, a weak acid (Ka1 = 6.0 × 10᎑10, 25 ⬚C), increases in basic solution as a result of successive deprotonation (30, 31). Predicting solubility of a compound in body fluids is more difficult; however, the same fundamental chemical relations apply. We recommend ref 32 for further reading on this topic. 2. One poisonous effect of arsenic compounds is inhibition of certain enzymes in cellular respiration. For a summary, see ref 8. For reviews, see ref 33 and 34. 3. Quoted and translated in ref 13. 4. Derivatives of arsonic acid were still in use in 1992, see ref 35. 500

Literature Cited 1. Stajic, M. In More Chemistry and Crime; Gerber, S. M., Saferstein, R., Eds.; American Chemical Society: Washington DC, 1997; pp 137–148. 2. Frost, D. V. Fed. Proc. 1967, 26, 194–208. 3. Frost, D. V. Adv. Exp. Med. Bio. 1977, 91, 259–279. 4. First/Final Report of The Royal Commission appointed to inquire into ARSENICAL POISONING from the consumption of beer and other articles of food or drink. I/III; His Majesty’s Stationery Office: London, 1901/1903. 5. Brit. Med. J. 1924, 1, 1149–1150. 6. Winship, K. A. Adverse Drug React. Acute Poisoning Rev. 1984, 3, 129–160. 7. Haller, J. S. Pharm. Hist. 1975, 17, 87–100. 8. Gorby, M. S. West. J. Med. 1988, 149, 308–315. 9. Perry, R. S. J. Am. J. Clin. Med. 1912, 19, 54–59. 10. Jolliffe, D. M. J. Royal Soc. Med. 1993, 86, 287–289. 11. Maclagan, C. Edinburgh Med. J.1864, 9, 200–207. 12. Webb, J. L. Enzyme and Metabolic Inhibitors; Academic Press: London, 1966; Vol. III, pp 595–793. 13. Chevallier, A. Boston Med. Surg. J. 1854, 51, 189–195. 14. Kesteven, W. B. Assoc. Med. J. 1856, 4, 721–722, 757–759, 808–812, 897. 15. Cloetta, M. Archiv für experimentelle Pathologie und Pharmakologie. 1906, 54, 196–205. 16. Goering, P. L.; Klaassen, C. D. In Metal Toxicology; Goyer, R. A., Klaassen, C. D., Waalkes, M. P., Eds.; Academic Press: London, 1995; pp 339–362. 17. Sneader, W. Drug Discovery. The Evolution of Modern Medicines; John Wiley & Sons: Chichester, U.K., 1985; p 248. 18. Bäumler, E. Paul Ehrlich. Scientist for Life; Holmes & Meier: New York, 1984; p 110. 19. Weismann, K. Sex. Trans. Dis. 1995, 3, 137–144. 20. Koch, R. In Great Chemists; Interscience Publ.: New York, 1961; pp 1041–1063. 21. Stokes, J. H.; Beerman, H.; Ingraham, N. R., Jr. Modern Clinical Syphilology. Diagnosis. Treatment. Case study; W. B. Saunders Company: London, 1944; pp 1245–1246. 22. Ni Dhubhghaill, O. M.; Sadler, P. J. Struc. Bond. 1991, 78, 129–190. 23. Levinson, A. S. J. Chem. Educ. 1977, 54, 98–99. 24. Scott, A. G.; Tait, A.; Turner, C. M. R. Exp. Parasitol. 1997, 86, 181–190. 25. König, A.; Wrazel, L.; Warrel, R. P., Jr.; Rivi, R.; Pandolfi, P. P.; Jakubowski, A.; Gabriove, J. L. Blood 1997, 90, 562–570. 26. Webb, J. L. Enzyme and Metabolic Inhibitors; Academic Press: London, 1966; Vol. III, p 595. 27. Guthrie, H. A. Introductory Nutrition, 2nd ed.; C. V. Mosby Company: London, 1983; pp 120–121. 28. Nielsen, F. H.; Uthus, E. O; Cornatzer, W. E. Bio.Trace Elem. Res. 1983, 5, 389–397. 29. Hutchinson, J. Trans. Path. Soc. London 1888, 39, 352–363. 30. Handbook of Chemistry and Physics, 72nd ed.; Lide, D. R., Ed.; CRC Press: Boston, 1991–1992. 31. Greenwood, N. N.; Earnshaw, A.; Chemistry of the Elements, 2nd ed.; Butterworth Heinemann: Oxford, 1997; p 574. 32. Pharmaceutics: The Science of Dosage Form Design, Aulton, M. E., Ed.; Churchill Livingstone: Edinburgh, 1988, pp 1–13, 135–173. 33. Stocken, L. A.; Thompson, R. H. S. Physiolo. Rev. 1949, 29, 168–194. 34. Peters, R. A. J. Roy. Inst. Pub. Hlth. and Hyg. 1952, 15, 89–103. 35. Ishiguro, S. App. Organomet. Chem. 1992, 6, 323–331.

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