Chemistry for Everyone
Discovery and Early Uses of Iodine Louis Rosenfeld Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 100161
Discovery Iodine was discovered by chance at the beginning of the 19th century. France was at war with many of her neighbors and needed enormous quantities of gunpowder to conduct its battles. In those times, the demand for ordinary saltpeter (potassium nitrate, KNO3), a major component of gunpowder, led to the formation of saltpeter “plantations” or nitriaries. These were common in France, Germany, and other countries. Potassium nitrate occurs naturally as crusts on the surface of the earth, on rocks and in caves, produced by the oxidation of nitrogenous matter in the presence of alkalis and alkaline earths. Closed off on land by the armies of Prussia and Austria and blockaded at sea by the British Navy, France’s supplies of imported nitrate were cut off. The nation was forced to expand its manufacture at home in specially constructed artificial niter beds. The natural conditions were simulated by exposing heaps of decaying organic matter, mixed with alkalis, to the action of atmospheric oxygen. The manufacture of saltpeter requires a plentiful supply of sodium carbonate (Na2CO3), which is obtained by extraction from wood ashes. Bernard Courtois (1777–1838), a manufacturer of saltpeter, was in the business of extracting sodium salts from wood ashes in metal vats. By leaching the ashes with water and evaporating the solution, the valuable sodium carbonate could be precipitated and recovered. After successive extractions there remained at the bottom of the vessels a thick mother liquor encrusted with insoluble material. From time to time it was necessary to clean out these sulfur-containing deposits with the aid of acid and heat. When Courtois substituted the ash of burned seaweed (kelp) for the wood ashes in the extraction process, it led to corrosion of his copper vats. Late in 1811, after adding a stronger than usual amount of sulfuric acid (which produced much heat), he noted an intense violetcolored vapor rising from the mixture. The vapor, condensing on the cooler parts of the vessel, formed a deposit of dark lustrous metal-like crystals, which corroded his kettles (1–3). The iodide in the seaweed ashes had been oxidized to iodine 2I ᎑ + H2SO4 → I 2 + SO32᎑ + H2O which then crystallized in the vats. After several months of investigation of the more obvious chemical properties and reactions of this new substance, Courtois had to abandon his research for lack of money. In 1812, he urged two chemist friends, Charles Bernard Desormes (1777–1862) and Nicolas Clément (1779–1841), to continue the research. Specimens were also given to Joseph Louis GayLussac (1778–1850), the most distinguished French chemist of his day, and to André M. Ampère (1775–1836). Identification On October 27, 1813, there arrived in Paris from England Sir Humphry Davy (1778–1829), the eminent English chemist, his wife, her maid, and Davy’s new laboratory assistant (also filling in as valet), Michael Faraday (1791–1867), aged 22. 984
En route to Italy, Davy had stopped in Paris to receive a medal awarded for his electrical discoveries. Safe passage had been approved by Napoleon. Although England and France were at war, the traffic of smugglers and cartels (unarmed ships commissioned in time of war to exchange prisoners or proposals between hostile powers) was enough to get scientific information back and forth as scientists continued to correspond. Ampère gave Davy a sample of the new substance and Davy got to work at once with some analytical tests. Considering it at first a compound of chlorine, he soon came to believe that it contained no chlorine but was a new element analogous to chlorine. (Davy always carried a compact chest of laboratory apparatus when he traveled. The scale of chemical operations was getting smaller. The furnaces of the 18th century were giving way to test tubes and spirit lamps. Although he was newly married, the portable chest of apparatus still went with him [4, 5]). The first public announcement of Courtois’s discovery was made on November 29, 1813, by Desormes and Clément at a meeting of the Imperial Institute of France. They described the principal properties but offered no decided opinion respecting its nature. On December 6, Gay-Lussac suggested that the new substance was either an element or a compound of oxygen. Davy sent off a paper to the Royal Society of London, dated December 10, 1813, describing his experiments and recognizing the similarities between the new substance and chlorine. He named it iodine (Greek: ioeides, violet colored), which was analogous to chlorine and fluorine (6 ). To Gay-Lussac it seemed as though Davy was elbowing in on his territory while his hosts were working on a detailed account of the new great discovery of French chemistry. What followed was a quarrel over priority rights. However, both investigators acknowledged Courtois as the discoverer of iodine. Gay-Lussac’s major publication on iodine was read on August 1, 1814. Gay-Lussac named the new element “iode”. In 1831 the Institut de France awarded Courtois a prize of 6000 francs. By this time, Courtois had given up the saltpeter business and, from the 1820s, attempted to make a living by preparing and selling iodine and iodine compounds. This business also failed, and he died in Paris in poverty (1). Thyroid Disorders of Iodine Deficiency A lack of iodine during infancy may cause a condition known as cretinism, in which mental and physical development is severely impaired. In adults and children, iodine deficiency leads to goiter and myxedema. Simple or endemic goiter (Latin: guttur, throat), enlargement of the thyroid gland, is the most common manifestation of iodine deficiency and is found particularly in mountainous regions and areas far from salt water. The lowest incidence of this disease occurs along seacoasts. In cases of severe and prolonged deficiency, there may be a deficit of thyroid hormones, resulting in myxedema (Greek: myxa, mucus). Myxedema is characterized by dry skin, loss of hair, puffy face, flabbiness and weakness of
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Chemistry for Everyone
muscles, weight gain, diminished energy, and mental sluggishness. The term was coined in 1877 by William Miller Ord (1834–1902) for the cretinoid condition in adult women described in 1873 by Sir William Withey Gull (1816–1890). Ord chose the name myxedema because chemical analysis of the swollen skin of the feet revealed fifty times the normal amount of mucin (7). Therapeutic Role of Seaweed and Burnt Sea Sponge Goiter has troubled mankind from time immemorial. The earliest record of goiter troubling humans appears in Chinese medical writings. About 36 centuries ago, the Chinese recognized goiter and the therapeutic effects of seaweed and burnt sea sponge in reducing its size or causing its disappearance, without any knowledge of iodine deficiency. The patient was advised to take one of these remedies at least twice yearly, in the spring and fall. The practice of Marine and Kimball (8) was in line with this regimen when, to prevent appearance of endemic goiter, they advised that school children be given sodium iodide (NaI) twice annually, about the first of May and December. These investigators were not trying to verify past practices, but their success provided a scientific explanation for an ancient practice that was not always effective and was not based on any knowledge of iodine deficiency. There is no evidence that the treatment with seaweed and burnt sea sponge was based on other than chance observation and empirical methods of prescribing. Many years later and centuries apart, Hippocrates, Galen, and Roger (Ruggiero) of the School of Salerno (late 12th century) recommended the same remedies without making reference to the origin or rationale of their treatment. Arnold of Villanova (1235–1311), Master of the School of Medicine in Montpellier, may have been the first to describe a preparation containing burnt sponge and seaweed as specific for goiter therapy. Apparently, throughout the centuries, favorable results were obtainable with these therapies (9). The authenticity of many of the early reports on goiter as a clinical entity is difficult to interpret because of the confusion found in early writings between goiter and tumors of the neck and the use of various terms as synonymous with goiter. The burnt-sponge remedy eventually found its way to England, where, in the mid-1700s, it was famed as the “Coventry Remedy”. For many years the Coventry recipe was held secret and exploited by the family of a Dr. Bate of that town. They had much success with it and gained a wide reputation and a considerable fortune. Only in 1779 was it disclosed that the essential ingredient was burnt sponge. Although the burnt sponge remedies were often totally ineffective, the treatment continued to be in favor and in constant use until the discovery of iodine in the early 19th century. Therapeutic Use of Iodine The enthusiasm of early 19th century physicians for the supposed therapeutic effects of iodine was indiscriminate and uncritical, and by no means confined to the treatment of goiter. The newly discovered element was applied to almost every case that resisted the routine therapy, and iodine was probably tried out as a remedy for most of the diseases known. In Europe and the United States, external and/or internal ad-
ministration of iodine generated claims of cure or relief for an astonishing array of diseases (10). Early settlers in the United States recognized the value of sea salt for treatment of goiter long before the discovery of iodine. At the close of the 17th century, the almost exclusive use of game meat, together with a lack of salt (NaCl), was generally believed by early New England settlers to be the cause of swelling of the neck. They recommended large quantities of sea salt, the only salt available to them (9). Modern Period of Investigation Iodine for the treatment of goiter was introduced in England by William Prout (1785–1850) (11). After iodine salts had been found in certain marine life-forms, it occurred to him that burnt sponge might owe its properties to the presence of iodine. In 1816, after trying hydriodate of potash (potassium iodate, KIO3) on himself in small doses and experiencing no ill effects, Prout suggested iodine treatment for goiter. This therapy was successfully adopted by John Elliotson (1791–1868) at St. Thomas’s Hospital in London early in 1819. Prout did not publish his findings until 1834. By then, the attention of the medical world had already been drawn to the value of iodine in goiter by the work of Jean François Coindet (1774–1834). In 1820, Coindet, a physician in Geneva, showed that iodine was the active principle of the burnt sponge remedy and established the relation of the curative properties of iodine to those of seaweed and burnt sponge. Giving iodine as an alcoholic tincture, 10 drops three times daily, Coindet observed that large, longstanding goiters began to soften and decrease in size after about 8 days of treatment and completely disappeared within 6 to 10 weeks in a great number of cases (12). Coindet announced his dramatic success with iodine in French and Swiss journals. An English translation appeared in a London journal (13). Neither he nor his followers restrained their enthusiasm for this new drug, and it became popular therapy for many diseases. However, as time went on, Coindet (14) became aware of the hazards of overdose and emphasized the need for great caution. He described iodism—characterized by tremor, palpitations, and weight loss—and was the first to draw attention to its development and to ascribe it to excessive dosage of iodine. Although he did not realize that his own prescriptions contained excessive quantities of iodine, he warned that treatment should be stopped when symptoms of toxic effects appeared. Coindet’s pioneer work was doomed to failure in the state of knowledge then existing. The doses of iodine used amounted to 2500 to 5000 times the optimum. Iodism was frequent. Fear of iodine-induced hyperactivity of the patient led to only short-term treatment with iodine. As a result, recurrence of goiter was common, and iodine therapy fell into disrepute (15). Prevention of Goiter As a result of Coindet’s initial therapeutic successes, it was proposed that goiter and cretinism might be due to iodine deficiency. The theory was not experimentally tested until the French chemist Gaspard Adolph Chatin (1813–1901) began his extensive series of iodine analyses. Between the years 1850
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and 1876, he performed comparative studies of the iodine content of air, water, soil, and vegetable and dairy products in many parts of Europe. His purpose was to compare the incidence of goiter in these areas with the estimated iodine intake of the relevant populations. He found that the iodine content of waters and foodstuffs grown in goitrous areas was less than in nongoiter areas, for example, seacoasts. Although his analytical methods were primitive, he was able to arrive at a plausible estimation of the average iodine intake of the inhabitants of the many areas investigated. Chatin was struck by the correlation between these estimates of low iodine intake and the local prevalence of goiter, and he concluded that iodine deficiency was the principal cause of goiter (16 ). Chatin recommended adding iodine to the water supply of goitrous areas. However, his data citing minute amounts of iodine did not fit the concepts of the time. Although the French Academy of Science accepted his findings concerning the distribution of iodine in water, soil, and plants, it did not accept the conclusion of a causal relationship between environmental iodine deficiency and the occurrence of endemic goiter (17 ). An 1852 Commission on the study of goiter could not accept the idea that such small amounts of iodine could have any physiological effect on the body. Furthermore, there were discrepancies in Chatin’s findings, such as the high iodine content in the water of the goitrous Lombardy plains in northern Italy. This was largely due to the low sensitivity of iodine analysis at that time. Chatin’s proposed programs of goiter prevention by the therapeutic use of iodine were abandoned. In 1876, a final paper on methodology entitled “On the nonsuccess in research on minimal amounts of iodine” emphasized certain experimental conditions essential for the successful detection of iodine (18). Chatin’s observations had to await two important events before they became acceptable: discovery in 1896 that the thyroid gland contains iodine (19), and the demonstration in 1912 that deficiency of trace factors can cause disease (20, 21). These two discoveries made the iodine-deficiency theory of goiter inherently plausible. Iodine Therapy Makes a Comeback As late as the 1890s, the role of the thyroid gland was still not known, and there were no tests yet available to study its function. In 1895 Adolf Magnus-Levy (1865–1955) introduced the experimental method of determining thyroid disturbances (22). He fed dried animal thyroids to normal men and made the fundamental observation that their metabolic rate was considerably increased. He also produced the first systematic study of the basal metabolism of normal individuals from childhood to old age and established that the function of the thyroid is to maintain the proper level of metabolism. The following year, Eugen Baumann (1846–1896) demonstrated the presence of iodine in an organic compound, which he called “Thyrojodin” (iodothyrin), as a normal constituent of the thyroid (23). This substance was effective in relieving the symptoms and signs of myxedema in patients with the spontaneous disease and in thyroidectomized animals. Iodized Salt in Treatment of Goiter Although credit for the introduction of iodized salt is usually given to workers early in the 20th century, actually 986
its use was recommended for the prevention of goiter in 1833 by Jean Baptiste Boussingault (1802–1887), a French mining engineer and agricultural chemist (24, 25). Influenced by his observations in the Andean highlands of South America, Boussingault made the first recommendation for the general use of iodized salt in goitrous areas after observing the absence of goiter in the lowland localities in Colombia. There, the inhabitants preferred a natural salt obtained from iodine-rich waters in an abandoned mine, which on analysis contained appreciable quantities of iodine. The authorities failed to implement his recommendations. On his return to France, Boussingault succeeded in introducing iodized salt for goiter prevention in badly affected districts. This campaign began to spread throughout Europe, but unfavorable reactions of iodism were frequent due to overenthusiastic use and overdose in therapy, as had been observed by Coindet. There was also a midcentury emphasis on the dangers of long-term administration of even minute quantities of iodine (26 ). Consequently, iodide prophylaxis was again discredited and abandoned. Recognition that the use of iodized salt in goitrous areas was the most convenient means for supplying dietary iodine to those in need of it was due almost entirely to the work of Marine and Kimball. In 1917 they initiated the first largescale program to prevent endemic goiter by means of iodide. Goiter incidence fell abruptly in the group of schoolgirls in Akron, Ohio, who were given sodium iodide regularly, compared with those who did not participate in the study (8, 27). The study unequivocally demonstrated the preventive and therapeutic effectiveness of small doses of iodine. Opponents of the program stopped it as an invasion of personal rights (28). However, the success of this experiment led to its repetition in Switzerland, where the use of an organic iodine preparation greatly reduced the incidence of goiter among school children and stimulated the reintroduction of iodized salt in Europe. Discovery and Synthesis of Thyroxine Studies on the chemistry of the thyroid gland prompted the extensive biochemical investigations that led to Edwin Calvin Kendall’s (1886–1972) isolation of crystalline thyroxine in 1914 (29, 30). Believing it to be a derivative of oxyindole, he named it thyroxyindole. Too bulky a word for every day usage, he shortened it to “thyroxin”. Since it was a basic substance, in order to conform with the accepted nomenclature of amino acids, it should be spelled “thyroxine”. The correct empirical formula of thyroxine (3,5,3′,5′-tetraiodothyronine) was determined by Harington in 1926 (31). The structure is shown below. I HO
I O
CH2
CH C
COOH
NH2 I
I
Thyroxine
The method of isolation was improved and a larger yield at much lower cost was obtained by Charles Robert Harington (1897–1972) in 1926 (32). Now material was available for chemical investigation. Harington proved that
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thyroxine was derived from tyrosine (β-p-hydroxyphenyl-αaminopropionic acid) and not, as Kendall believed, from tryptophan (β-3-indole-α-aminopropionic acid) (see structures). CH2
HO
CH2
CH
CH
NH2
N H
Tyrosine
Tryptophan
Thyroxine was synthesized in 1927 by Harington and George Barger (1878–1939) (33). It was the second hormone isolated in pure form. Epinephrine (see structure) had been isolated and named by John Jacob Abel (1857–1938) in 1898. HO CH C
HO
CH2
NH
CH3
OH
Epinephrine
It was later discovered that the thyroid is able to synthesize a second hormone more active than thyroxine. In the early 1940s two new analytic tools became available: radioactive isotopes of iodine and paper chromatography. With their use, Gross and Pitt-Rivers identified the second hormone as 3,5,3′-L-triiodothyronine (see structure) (34). On the basis of the greater potency of triiodothyronine, they suggested that this is the peripheral hormone and thyroxine is its precursor. I HO
I O
CH2
CH C
1. Requests for reprints should be addressed to Louis Rosenfeld at 1417 E. 52nd St., Brooklyn, NY 11234.
COOH
NH2
COOH
Note
COOH
NH2 I
Triiodothyronine
Summary The ancient Chinese recognized goiter and the therapeutic effects of burnt sponge and seaweed in reducing its size or causing its disappearance. The modern use of iodine in the prevention of goiter dates from 1830, when it was proposed that goiter is an iodine deficiency disease. But unfavorable symptoms were frequent, owing to overdose of iodine. Iodine’s presence in organic combination as a normal constituent of the thyroid was established in 1896 and revived its use in treatment and prevention of goiter. This history of the discovery and early uses of iodine mixes ancient practices, secret recipes, accidental scientific discovery, professional rivalry, and the use and misuse of medical discovery against a backdrop of the impact of warfare in the development of science. Careful scientific work eventually led to identification, analysis, and synthesis of the primary biochemical substance responsible for iodine metabolism. The interplay of these disparate forces could be a subject for classroom discussion of other examples from the history of science illustrating the impact of accidental scientific discovery on the health and economic vitality of a society.
Literature Cited 1. Costa, A. B. In Dictionary of Scientific Biography; Gillispie, C. C., Ed.; Charles Scribner’s Sons: New York, 1971; Vol. 3, p 455. 2. Courtois, B. Ann. Chim. 1813, 88, 304–310. 3. Kelly, F. C. Proc. R. Soc. Med. 1961, 54, 831–836. 4. Knight, D. M. In Dictionary of Scientific Biography; Gillispie, C. C., Ed.; Charles Scribner’s Sons: New York, 1971; Vol. 3, pp 598–604. 5. Knight, D. Humphry Davy. Science & Power; Blackwell: Oxford, 1992; pp 94, 96, 97, 99–100. 6. Davy, H. Philos. Trans. R . Soc. London 1814, 104, 74–93. 7. Rolleston, H. D. The Endocrine Organs in Health and Disease with an Historical Review; Oxford University Press: London, 1936; p 175. 8. Marine, D.; Kimball, O. P. J. Lab. Clin. Med. 1917, 3, 40–49. 9. Spear, D. B.; McGavack, T. H. In McGavack, T. H. The Thyroid; Mosby: St. Louis, 1951; pp 18, 22. 10. Hobson, S. J. Trans. Med. Soc. State of NY 1835, 2, 261–315. 11. Prout, W. Chemistry, Meteorology, and the Function of Digestion, Considered with Reference to Natural Theology; Carey, Lea & Blanchard: Philadelphia, 1834; pp 75–76 footnote. 12. Coindet, J. F. Ann. Chim. Phys. 1820, 15, 49–59. 13. Coindet, J. F. London Med. Phys. J. 1820, 44, 486–489. 14. Coindet, J. F. Bibl. universelle Sci. Arts (Genève) 1821, 16, 140– 152. 15. Matovinovic, J.; Ramalingaswami, V. Bull. WHO 1958, 18, 233–253. 16. Chatin, A. C. R. Hebd. Seances Acad. Sci. 1852, 34, 51–54. 17. Pitt-Rivers, R. In Hormonal Proteins and Peptides, Thyroid Hormones, 6th ed.; Li Choch Hao, Ed.; Academic: New York, 1978; pp 394–395. 18. Chatin, A. C. R. Hebd. Seances Acad. Sci. 1876, 82, 128–132. 19. Baumann, E. Hoppe-Seyler’s Z. Physiol. Chem. 1895–1896, 21, 319–330. 20. Hopkins, F. G. J. Physiol. 1912, 44, 425–460. 21. Rosenfeld, L. Clin. Chem. 1997, 43, 680–685. 22. Magnus-Levy, A. Berl. Klin. Wchschr. 1895, 32, 650–652. 23. Baumann, E. Hoppe-Seyler’s Z. Physiol. Chem. 1896, 22, 1–17. 24. Boussingault, J. B. Ann. Chim. Phys. 1833, 54, 163–177. 25. Boussingault, J. B. Ann. Chim. Phys. 1831, 48, 41–69. 26. Rilliet, F. Bull. Acad. Natl. Med. 1858, 24, 23–27. 27. Marine, D.; Kimball, O. P. Arch. Intern. Med. 1920, 25, 661– 672. 28. Kohn, L. A. Bull. Hist. Med. 1975, 49, 389–399. 29. Kendall, E. C. J. Am. Med. Assoc. 1915, 64, 2042–2043. Reprinted in J. Am. Med. Assoc. 1983, 250, 2045–2046. 30. Kendall, E. C. Trans. Assoc. Am. Physicians 1915, 30, 420–449. 31. Harington, C. R. Biochem. J. 1926, 20, 300–313. 32. Harington, C. R. Biochem. J. 1926, 20, 293–299. 33. Harington, C. R.; Barger, G. Biochem. J. 1927, 21, 169–181. 34. Gross, J.; Pitt-Rivers, R. Lancet 1952, 1, 439–441.
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