- Email: [email protected]
Blue Gods, Blue Oil, and Blue People
Historical Vignette Blue Gods, Blue Oil, and Blue People VIRGIL F. FAIRBANKS,
M.D.
Studies of the composition of coal tar, which began in Prussia in 1834, profoundly affected the economies of Germany, Great Britain, India, and the rest of the world, as well as medicine and surgery. Such effects include the collapse of the profits of the British indigo monopoly, the growth in economic power of Germany based on coal tar chemistry, and an economic crisis in India that led to more humane tax laws and, ultimately, the independence of India and the end of the British Empire. Additional consequences were the development of antiseptic surgery and the synthesis of a wide variety of useful drugs that have eradi-
cated infections and alleviated pain. Many of these drugs, particularly the commonly used analgesics, sulfonamides, sulfones, and local anesthetics, are derivatives of aniline, originally called "blue oil" or "kyanol." Some of these aniline derivatives, however, have also caused aplastic anemia, agranulocytosis, and methemoglobinemia (that is, "blue people"). Exposure to aniline drugs, particularly when two or three aniline drugs are taken concurrently, seems to be the commonest cause of methemoglobinemia today. (Mayo Clin Proc 1994; 69:889-892)
When Julius Caesar invaded Britain, his Roman legions encountered a blue-skinned race, fearsome in battle. They were the Keltic Picts, who painted and tattooed themselves with an indigo-like extract from the woad plant. Blue relates, in religion and mythology, to deity. In Muslim art and designs, in Persian carpets, and in mosques, blue symbolizes heaven. The old Norse god Odin was distinguished by his blue cape. The Hindu god Krishna is portrayed as being as blue as indigo, a persistent generalized cyanosis that, according to tradition, resulted from the bite of a cobra (Prakash UBS. Personal communication).1 Perhaps Krishna had congenital methemoglobinemia, or perhaps the indigo hue of Krishna only symbolized his celestial nature and his immunity to a venom lethal to mortals.
Throughout history, the most costly dye, Tyrian purple, was extracted in minute amount from thousands of snails of the genus Murex. Only emperors and kings could wear it; hence, it was the "royal purple." Nonetheless, the most popular dye was indigo; it was extracted from fermented stems and leaves of plants of the genus Indigofera, which are indigenous to India and Burma (Fig. 1). For more than a century, the indigo trade was a monopoly of Great Britain. Indigofera plants were also introduced into the Carolinas, Georgia, British Florida, and the Caribbean. Indigo became one of the major exports of the American colonies. In little more than a decade during the late 18th century, 17 million pounds of processed indigo were shipped from South Carolina to England.2
INDIGO Indigo is "navy blue," the color of naval, military, and police uniforms, of blue jeans, and of men's dress suits. It is the color of the night and evening sky. It is the color of the blueskinned Tuaregs, nomads of the Sahara, whose clothing stains their skin because the dye has not been well mordanted. More prosaically, indigo is known in the dye industry as "vat blue dye No. 1."
COAL TAR During the 19th century, European and American cities were lit by gas lamps that burned illuminating gas, principally carbon monoxide, a by-product of the conversion of coal to coke for the manufacture of steel. Another by-product, which was considered worthless, was coal tar. During the 1830s, Friedlieb F. Runge, a 40-year-old chemist, had been given funds for unspecified research and facilities in an old castle, which had been converted to a chemical factory, in Oranienburg, approximately 20 kilometers north of Berlin.3·4 He wondered whether anything could be done with the huge vats of coal tar that were accumulating. The coal tar was too messy to dump. Nobody wanted it; nobody knew what to do with it. Prussia had a toxic waste disposal problem.
From the Division of Hematology and Internal Medicine and Division of Metabolic and Hématologie Biochemistry, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. V. F. Fairbanks, Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1994; 69:889-892
889
© 1994 Mayo Foundation for Medical Education and Research
890
BLUE GODS, BLUE OIL, AND BLUE PEOPLE
\
/ /
H«-0
Fig. 1. Structure of indigo. Heavy lines show two aniline moieties linked by four carbon butynedione. Indigo is, by weight, approximately 70% aniline. It is readily converted to aniline with heating.
Runge obtained fractions from coal tar that he characterized and named: carbolic acid (he was the first to identify phenol), rosolie acid (still used by this name in the dye industry but better known as pararosolic acid or aurin), pyrrole (dear to porphyrin chemists and "hemoglobinologists"), leukol (a white oily substance later renamed quinoline), brunolic acid (a brownish oily substance, perhaps anthracene), and kyanol (from Greek, blue oil), a dark violetblue oily distillate that reversibly formed colorless crystals on acidification. In 1834, he reported that "coal tar seems to be pretty rich in kyanol."5 Forty years later, when the structure of kyanol was shown to be aminobenzene, it was renamed aniline (nil, an Arabic adjective, means "the blue"; the Nile is also "the blue" river of Egypt). During the course of his research, Runge devised the analytic technique of paper chromatography, which is still widely used 1 'h centuries later. ANILINE Runge may have been the first to recognize a relationship between indigo and blue oil/kyanol/aniline. Allegedly, he urged that indigo be synthesized commercially from kyanol.3 The profits of the indigo trade would then flow to Prussia, not to England; however, in 1834, Kekulé had not yet postulated the ring structure of benzene (and of phenol and aniline). Neither Runge nor his contemporaries could hypothesize the structures of kyanol, carbolic acid, pyrrole, leukol, rosolie acid, or indigo. That Runge had extracted, named, and characterized many of the components of coal tar was enough. In 1834, the synthesis of indigo from coal tar, or from kyanol, was beyond the ability of any chemist. By 1896, the structures of benzene, phenol, aniline, indigo, and numerous other substances had been elucidated, and German chemists, led by Bayer, had begun the largescale manufacture of indigo from aniline (in turn derived from coal tar). Synthetic indigo proved superior to natural
Mayo Clin Proc, September 1994, Vol 69
indigo in stability, purity, and reproducibility of color. In addition, no matter how low the price of British indigo was driven, synthetic indigo could be sold for less, and a profit could still be earned. Coal tar had become an indispensable raw material instead of a messy liability. Germany rapidly captured world trade in indigo. Furthermore, because Tyrian purple is merely dibromoindigo, easily synthesized from aniline and no longer costly, anybody could wear the royal purple. Subsequently, an enormous variety of beautiful dyes were being marketed by the German industry—the aniline dyes, also know as coal tar dyes. The world became more colorful; aniline and other coal tar derivatives banished drabness. The once highly profitable British indigo trade collapsed. In 1897, British merchants had exported almost 10,000 tons of processed indigo from India. By 1911, annual British exports of natural indigo had dwindled to 860 tons, whereas Germany had exported 220,000 tons of synthetic indigo.3 Subsequently, because exports of synthetic dyes to Great Britain and the United States threatened British and American chemical industries, both countries established high protective tariffs that succeeded in decreasing imports of aniline dyes and other chemicals from Germany. CRISIS IN INDIA The collapse of the market for British indigo dramatically affected India, the natural home of the Indigofera species, particularly the states of Bengal and Bihar.5 Indeed, the end of the indigo plantation system in India was the beginning of the end of the British Raj and thus of the British Empire. Mohandas K. Gandhi, a young lawyer who had returned from South Africa in 1915 to his native India, was a participant in this crisis. Gandhi later wrote the following in his autobiography:6 Champaran (a district in Bihar state)...used to be full of indigo plantations until the year 1917. The Champaran tenant was obliged to plant three out of every twenty parts of his land with indigo for his (British) landlord. This...was known as the tinkathia system... .1 had seen packets of indigo, but little dreamed that it was grown and manufactured in Champaran at great hardship to thousands of agriculturists. After indigo was no longer a viable commercial crop, the tenant farmers were required to pay taxes in cash rather than in raw indigo, a condition that added to their poverty and hardship, particularly during a time of drought and depression. Gandhi went to Champaran, met with the field workers, and observed their suffering (a scene faithfully portrayed in the movie Gandhi). He interceded on the workers' behalf and organized civil disobedience in protest. He was arrested for civil disobedience and brought to trial; he pled
Mayo Clin Proc, September 1994, Vol 69
guilty and was convicted, but his sentence was dismissed. The trial had become a trial of the imperial system. The trial of Gandhi in Champaran led to the passage of the Agrarian Act, which abolished the powers of the British landowners and mandated compensation from them for prior injustices to the workers. Of this extraordinary outcome, Gandhi wrote:
BLUE GODS, BLUE OIL, AND BLUE PEOPLE
891
anodyne. Unfortunately, acetanilide caused many cases of methemoglobinemia, agranulocytosis, and fatal aplastic anemia; thus, it is no longer available for human use. Nonetheless, generations of less toxic aniline (anilide) drugs have been manufactured, including antipyrine (no longer available), indomethacin, dipyrone, phenacetin, acetaminophen, all the sulfonamides, all the sulfones, phenazopyridine (widely prescribed as a urinary tract analgesic ...the tinkathia system which had been in existence for about a and best known as Pyridium), and most of the local anesthetcentury was thus abolished, and the planters' raj came to an ics (including benzocaine, lidocaine, and procaine; cocaine end.. .the superstition that the stain of indigo could never be washed is an exception). All of these anilides are capable of inducout was exploded. ing methemoglobinemia.8 Indeed, exposure to these substances is by far the commonest cause of methemoglobinThe interval between the publication of Runge's studies emia today. on coal tar and the first synthesis of indigo from coal tar was 63 years; from the latter to the passage of the Agrarian Act METHEMOGLOBINEMIA was only 20 years. In another 30 years, India attained Not all of these aniline drugs have a high propensity for complete independence. Not long thereafter, the British causing methemoglobinemia. Fortunately, lethal blood Empire ceased to exist, its place taken by a loose alliance of dyscrasias are rare except with use of acetanilide. Dapsone, fully independent nations—the British Commonwealth. which is dianilide sulfone, seems to cause some degree of methemoglobinemia in most persons. Conversely, not a ANTISEPTIC SURGERY single case of methemoglobinemia has been reported with The research on coal tar by Runge, and by chemists who ingestion of only acetaminophen (p-hydroxy acetyl anilide, followed him, had an equally profound effect on the prac- paracetamol, or Tylenol), even with massive suicidal doses, tice of medicine and surgery. Phenol, from coal tar, was an astonishing fact in view of its close chemical relationship used extensively in Europe for treating sewage. Thus, dur- to acetanilide, phenacetin, and aniline. Nonetheless, ing the 1860s, when Joseph Lister, a young surgeon, con- methemoglobinemia may occur in persons who are taking templated how to decrease the frequency and severity of acetaminophen with other aniline congeners such as sulfonapostoperative infections, inexpensive phenol was readily mides or phenazopy ridine. available. The use of phenol in surgical antisepsis was Our laboratory received a specimen of blood for metherevolutionary; postoperative infections that had been respon- moglobin assay from a patient who, while taking acetaminsible for high rates of postoperative morbidity and mortality ophen and phenazopyridine, underwent spinal anesthesia in became infrequent.7 Runge's research on coal tar had al- preparation for herniorrhaphy. He soon became unconscious lowed Lister to change forever the practice and outcomes of and unresponsive, and he was indigo blue—as blue as suVgery. Krishna. His methemoglobin concentration was 44%. ForRunge died in 1867, the year that Lister published his tunately, he responded rapidly and completely to intravenous observations on antiseptic surgery. Runge could hardly have administration of méthylène blue. foreseen the enormous consequences of his research on inPhysicians, and particularly anesthesiologists, must bedustry, commerce, the course of an empire, and the practice come aware of the hazard of concurrent administration of of medicine and surgery, because all these developments more than one aniline drug to patients. Even with topical came during later generations. application of benzocaine, absorption of this substance may be sufficient to induce methemoglobinemia. One need not DRUGS FROM COAL TAR invoke methemoglobin reductase deficiency. While German chemists were destroying the profits of the British Empire by manufacturing synthetic indigo, they were EPILOGUE also beginning the synthesis of new pharmaceuticals. Ni- It is a long and colorful circuit from the blue god Krishna to trobenzene, which forms from the condensation of benzene the blue extract of the Indigofera plant, to Runge's blue oil/ (distilled from coal tar) and nitric acid, proved to be excep- kyanol/aniline, to the synthesis of indigo from aniline, to tionally versatile in the synthesis of a wide variety of useful aniline drugs, to people made as blue as Krishna by an drugs. From the reduction of nitrobenzene, aniline became overdose of aniline drugs and their successful treatment, the common denominator of all such drugs. Acetanilide paradoxically, with another aniline derivative, méthylène (acetyl anilide) was introduced in 1886 as an antipyretic and blue.
892
BLUE GODS, BLUE OIL, AND BLUE PEOPLE
The far-reaching effect of a scientist's solitary research on the course of history is well exemplified by Runge's coal tar studies. ACKNOWLEDGMENT I thank Donald S. Pady, director of the historical unit of the Mayo Medical Library, for locating the original article by Runge.
REFERENCES
1. Frazer JG. The Golden Bough: A Study in Magic and Religion. 3rd ed. New York: St. Martin's Press, 1990
ARCHAEOtOOiCAL
Medical Mythology: Yaksha A
15^
MOTV9I
POSTAGE
Marc A. Shampo, Ph.D., and Robert A. Kyle M.D.
In the mythology of India, the yakshas were supernatural beings who seceded from the demons and took over the mountain areas. They were similar to gnomes or fairies and were worshipped by the rural peoples. In ancient times, their cult was widespread, but they lost their importance when the great gods of Hinduism assumed significance. The yakshas
Mayo Clin Proc, September 1994, Vol 69
2. US Bureau of the Census. The Statistical History of the United States From Colonial Times to the Present. New York: Basic Books, 1976 3. Schenzinger KA. Anilin. Munich: Wilhelm Andermann Verlag, 1957 4. Gillespie CC, editor. Dictionary of Scientific Biography. Vol 11. New York: Charles Scribner's Sons, 1975: 615-616 5. Runge FF. Ueber einige Produkte der Steinkohlendestillation. AnnPhysChem 1834;31:65-80 6. Gandhi MK. Autobiography: The Story of My Experiments With Truth. (Translated by M Desai.) London: Phoenix Press, 1949 7. Lister J. On the antiseptic principle of the practice of surgery. BMJ 1867;2:246-248 8. Dinneen SF, Mohr DN, Fairbanks VF. Methemoglobinemia from topically applied anesthetic spray. Mayo Clin Proc 1994; 69:886-888
were generally benevolent to humans and were said to be the custodians of treasures hidden in the earth and in the roots of trees. The female yaksha, or yakshi, was often depicted as a heavily jeweled fertility figure. Chief among the yakshas was Kubera, who ruled the mythical Himalayan kingdom of Alaka and was associated with the earth, mountains, and all the treasures (such as minerals and jewels) that lay underground. He was guardian of the northern lands and was usually depicted as a potbellied dwarf holding a moneybag or pomegranate (the symbol of fertility). In art, sculptures of yakshas are among the earliest representations of deities. These ancient sculptures usually portray the yakshas as large, potbellied figures. The yaksha is depicted on this stamp issued by India in 1961.
M.D.
Studies of the composition of coal tar, which began in Prussia in 1834, profoundly affected the economies of Germany, Great Britain, India, and the rest of the world, as well as medicine and surgery. Such effects include the collapse of the profits of the British indigo monopoly, the growth in economic power of Germany based on coal tar chemistry, and an economic crisis in India that led to more humane tax laws and, ultimately, the independence of India and the end of the British Empire. Additional consequences were the development of antiseptic surgery and the synthesis of a wide variety of useful drugs that have eradi-
cated infections and alleviated pain. Many of these drugs, particularly the commonly used analgesics, sulfonamides, sulfones, and local anesthetics, are derivatives of aniline, originally called "blue oil" or "kyanol." Some of these aniline derivatives, however, have also caused aplastic anemia, agranulocytosis, and methemoglobinemia (that is, "blue people"). Exposure to aniline drugs, particularly when two or three aniline drugs are taken concurrently, seems to be the commonest cause of methemoglobinemia today. (Mayo Clin Proc 1994; 69:889-892)
When Julius Caesar invaded Britain, his Roman legions encountered a blue-skinned race, fearsome in battle. They were the Keltic Picts, who painted and tattooed themselves with an indigo-like extract from the woad plant. Blue relates, in religion and mythology, to deity. In Muslim art and designs, in Persian carpets, and in mosques, blue symbolizes heaven. The old Norse god Odin was distinguished by his blue cape. The Hindu god Krishna is portrayed as being as blue as indigo, a persistent generalized cyanosis that, according to tradition, resulted from the bite of a cobra (Prakash UBS. Personal communication).1 Perhaps Krishna had congenital methemoglobinemia, or perhaps the indigo hue of Krishna only symbolized his celestial nature and his immunity to a venom lethal to mortals.
Throughout history, the most costly dye, Tyrian purple, was extracted in minute amount from thousands of snails of the genus Murex. Only emperors and kings could wear it; hence, it was the "royal purple." Nonetheless, the most popular dye was indigo; it was extracted from fermented stems and leaves of plants of the genus Indigofera, which are indigenous to India and Burma (Fig. 1). For more than a century, the indigo trade was a monopoly of Great Britain. Indigofera plants were also introduced into the Carolinas, Georgia, British Florida, and the Caribbean. Indigo became one of the major exports of the American colonies. In little more than a decade during the late 18th century, 17 million pounds of processed indigo were shipped from South Carolina to England.2
INDIGO Indigo is "navy blue," the color of naval, military, and police uniforms, of blue jeans, and of men's dress suits. It is the color of the night and evening sky. It is the color of the blueskinned Tuaregs, nomads of the Sahara, whose clothing stains their skin because the dye has not been well mordanted. More prosaically, indigo is known in the dye industry as "vat blue dye No. 1."
COAL TAR During the 19th century, European and American cities were lit by gas lamps that burned illuminating gas, principally carbon monoxide, a by-product of the conversion of coal to coke for the manufacture of steel. Another by-product, which was considered worthless, was coal tar. During the 1830s, Friedlieb F. Runge, a 40-year-old chemist, had been given funds for unspecified research and facilities in an old castle, which had been converted to a chemical factory, in Oranienburg, approximately 20 kilometers north of Berlin.3·4 He wondered whether anything could be done with the huge vats of coal tar that were accumulating. The coal tar was too messy to dump. Nobody wanted it; nobody knew what to do with it. Prussia had a toxic waste disposal problem.
From the Division of Hematology and Internal Medicine and Division of Metabolic and Hématologie Biochemistry, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. V. F. Fairbanks, Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1994; 69:889-892
889
© 1994 Mayo Foundation for Medical Education and Research
890
BLUE GODS, BLUE OIL, AND BLUE PEOPLE
\
/ /
H«-0
Fig. 1. Structure of indigo. Heavy lines show two aniline moieties linked by four carbon butynedione. Indigo is, by weight, approximately 70% aniline. It is readily converted to aniline with heating.
Runge obtained fractions from coal tar that he characterized and named: carbolic acid (he was the first to identify phenol), rosolie acid (still used by this name in the dye industry but better known as pararosolic acid or aurin), pyrrole (dear to porphyrin chemists and "hemoglobinologists"), leukol (a white oily substance later renamed quinoline), brunolic acid (a brownish oily substance, perhaps anthracene), and kyanol (from Greek, blue oil), a dark violetblue oily distillate that reversibly formed colorless crystals on acidification. In 1834, he reported that "coal tar seems to be pretty rich in kyanol."5 Forty years later, when the structure of kyanol was shown to be aminobenzene, it was renamed aniline (nil, an Arabic adjective, means "the blue"; the Nile is also "the blue" river of Egypt). During the course of his research, Runge devised the analytic technique of paper chromatography, which is still widely used 1 'h centuries later. ANILINE Runge may have been the first to recognize a relationship between indigo and blue oil/kyanol/aniline. Allegedly, he urged that indigo be synthesized commercially from kyanol.3 The profits of the indigo trade would then flow to Prussia, not to England; however, in 1834, Kekulé had not yet postulated the ring structure of benzene (and of phenol and aniline). Neither Runge nor his contemporaries could hypothesize the structures of kyanol, carbolic acid, pyrrole, leukol, rosolie acid, or indigo. That Runge had extracted, named, and characterized many of the components of coal tar was enough. In 1834, the synthesis of indigo from coal tar, or from kyanol, was beyond the ability of any chemist. By 1896, the structures of benzene, phenol, aniline, indigo, and numerous other substances had been elucidated, and German chemists, led by Bayer, had begun the largescale manufacture of indigo from aniline (in turn derived from coal tar). Synthetic indigo proved superior to natural
Mayo Clin Proc, September 1994, Vol 69
indigo in stability, purity, and reproducibility of color. In addition, no matter how low the price of British indigo was driven, synthetic indigo could be sold for less, and a profit could still be earned. Coal tar had become an indispensable raw material instead of a messy liability. Germany rapidly captured world trade in indigo. Furthermore, because Tyrian purple is merely dibromoindigo, easily synthesized from aniline and no longer costly, anybody could wear the royal purple. Subsequently, an enormous variety of beautiful dyes were being marketed by the German industry—the aniline dyes, also know as coal tar dyes. The world became more colorful; aniline and other coal tar derivatives banished drabness. The once highly profitable British indigo trade collapsed. In 1897, British merchants had exported almost 10,000 tons of processed indigo from India. By 1911, annual British exports of natural indigo had dwindled to 860 tons, whereas Germany had exported 220,000 tons of synthetic indigo.3 Subsequently, because exports of synthetic dyes to Great Britain and the United States threatened British and American chemical industries, both countries established high protective tariffs that succeeded in decreasing imports of aniline dyes and other chemicals from Germany. CRISIS IN INDIA The collapse of the market for British indigo dramatically affected India, the natural home of the Indigofera species, particularly the states of Bengal and Bihar.5 Indeed, the end of the indigo plantation system in India was the beginning of the end of the British Raj and thus of the British Empire. Mohandas K. Gandhi, a young lawyer who had returned from South Africa in 1915 to his native India, was a participant in this crisis. Gandhi later wrote the following in his autobiography:6 Champaran (a district in Bihar state)...used to be full of indigo plantations until the year 1917. The Champaran tenant was obliged to plant three out of every twenty parts of his land with indigo for his (British) landlord. This...was known as the tinkathia system... .1 had seen packets of indigo, but little dreamed that it was grown and manufactured in Champaran at great hardship to thousands of agriculturists. After indigo was no longer a viable commercial crop, the tenant farmers were required to pay taxes in cash rather than in raw indigo, a condition that added to their poverty and hardship, particularly during a time of drought and depression. Gandhi went to Champaran, met with the field workers, and observed their suffering (a scene faithfully portrayed in the movie Gandhi). He interceded on the workers' behalf and organized civil disobedience in protest. He was arrested for civil disobedience and brought to trial; he pled
Mayo Clin Proc, September 1994, Vol 69
guilty and was convicted, but his sentence was dismissed. The trial had become a trial of the imperial system. The trial of Gandhi in Champaran led to the passage of the Agrarian Act, which abolished the powers of the British landowners and mandated compensation from them for prior injustices to the workers. Of this extraordinary outcome, Gandhi wrote:
BLUE GODS, BLUE OIL, AND BLUE PEOPLE
891
anodyne. Unfortunately, acetanilide caused many cases of methemoglobinemia, agranulocytosis, and fatal aplastic anemia; thus, it is no longer available for human use. Nonetheless, generations of less toxic aniline (anilide) drugs have been manufactured, including antipyrine (no longer available), indomethacin, dipyrone, phenacetin, acetaminophen, all the sulfonamides, all the sulfones, phenazopyridine (widely prescribed as a urinary tract analgesic ...the tinkathia system which had been in existence for about a and best known as Pyridium), and most of the local anesthetcentury was thus abolished, and the planters' raj came to an ics (including benzocaine, lidocaine, and procaine; cocaine end.. .the superstition that the stain of indigo could never be washed is an exception). All of these anilides are capable of inducout was exploded. ing methemoglobinemia.8 Indeed, exposure to these substances is by far the commonest cause of methemoglobinThe interval between the publication of Runge's studies emia today. on coal tar and the first synthesis of indigo from coal tar was 63 years; from the latter to the passage of the Agrarian Act METHEMOGLOBINEMIA was only 20 years. In another 30 years, India attained Not all of these aniline drugs have a high propensity for complete independence. Not long thereafter, the British causing methemoglobinemia. Fortunately, lethal blood Empire ceased to exist, its place taken by a loose alliance of dyscrasias are rare except with use of acetanilide. Dapsone, fully independent nations—the British Commonwealth. which is dianilide sulfone, seems to cause some degree of methemoglobinemia in most persons. Conversely, not a ANTISEPTIC SURGERY single case of methemoglobinemia has been reported with The research on coal tar by Runge, and by chemists who ingestion of only acetaminophen (p-hydroxy acetyl anilide, followed him, had an equally profound effect on the prac- paracetamol, or Tylenol), even with massive suicidal doses, tice of medicine and surgery. Phenol, from coal tar, was an astonishing fact in view of its close chemical relationship used extensively in Europe for treating sewage. Thus, dur- to acetanilide, phenacetin, and aniline. Nonetheless, ing the 1860s, when Joseph Lister, a young surgeon, con- methemoglobinemia may occur in persons who are taking templated how to decrease the frequency and severity of acetaminophen with other aniline congeners such as sulfonapostoperative infections, inexpensive phenol was readily mides or phenazopy ridine. available. The use of phenol in surgical antisepsis was Our laboratory received a specimen of blood for metherevolutionary; postoperative infections that had been respon- moglobin assay from a patient who, while taking acetaminsible for high rates of postoperative morbidity and mortality ophen and phenazopyridine, underwent spinal anesthesia in became infrequent.7 Runge's research on coal tar had al- preparation for herniorrhaphy. He soon became unconscious lowed Lister to change forever the practice and outcomes of and unresponsive, and he was indigo blue—as blue as suVgery. Krishna. His methemoglobin concentration was 44%. ForRunge died in 1867, the year that Lister published his tunately, he responded rapidly and completely to intravenous observations on antiseptic surgery. Runge could hardly have administration of méthylène blue. foreseen the enormous consequences of his research on inPhysicians, and particularly anesthesiologists, must bedustry, commerce, the course of an empire, and the practice come aware of the hazard of concurrent administration of of medicine and surgery, because all these developments more than one aniline drug to patients. Even with topical came during later generations. application of benzocaine, absorption of this substance may be sufficient to induce methemoglobinemia. One need not DRUGS FROM COAL TAR invoke methemoglobin reductase deficiency. While German chemists were destroying the profits of the British Empire by manufacturing synthetic indigo, they were EPILOGUE also beginning the synthesis of new pharmaceuticals. Ni- It is a long and colorful circuit from the blue god Krishna to trobenzene, which forms from the condensation of benzene the blue extract of the Indigofera plant, to Runge's blue oil/ (distilled from coal tar) and nitric acid, proved to be excep- kyanol/aniline, to the synthesis of indigo from aniline, to tionally versatile in the synthesis of a wide variety of useful aniline drugs, to people made as blue as Krishna by an drugs. From the reduction of nitrobenzene, aniline became overdose of aniline drugs and their successful treatment, the common denominator of all such drugs. Acetanilide paradoxically, with another aniline derivative, méthylène (acetyl anilide) was introduced in 1886 as an antipyretic and blue.
892
BLUE GODS, BLUE OIL, AND BLUE PEOPLE
The far-reaching effect of a scientist's solitary research on the course of history is well exemplified by Runge's coal tar studies. ACKNOWLEDGMENT I thank Donald S. Pady, director of the historical unit of the Mayo Medical Library, for locating the original article by Runge.
REFERENCES
1. Frazer JG. The Golden Bough: A Study in Magic and Religion. 3rd ed. New York: St. Martin's Press, 1990
ARCHAEOtOOiCAL
Medical Mythology: Yaksha A
15^
MOTV9I
POSTAGE
Marc A. Shampo, Ph.D., and Robert A. Kyle M.D.
In the mythology of India, the yakshas were supernatural beings who seceded from the demons and took over the mountain areas. They were similar to gnomes or fairies and were worshipped by the rural peoples. In ancient times, their cult was widespread, but they lost their importance when the great gods of Hinduism assumed significance. The yakshas
Mayo Clin Proc, September 1994, Vol 69
2. US Bureau of the Census. The Statistical History of the United States From Colonial Times to the Present. New York: Basic Books, 1976 3. Schenzinger KA. Anilin. Munich: Wilhelm Andermann Verlag, 1957 4. Gillespie CC, editor. Dictionary of Scientific Biography. Vol 11. New York: Charles Scribner's Sons, 1975: 615-616 5. Runge FF. Ueber einige Produkte der Steinkohlendestillation. AnnPhysChem 1834;31:65-80 6. Gandhi MK. Autobiography: The Story of My Experiments With Truth. (Translated by M Desai.) London: Phoenix Press, 1949 7. Lister J. On the antiseptic principle of the practice of surgery. BMJ 1867;2:246-248 8. Dinneen SF, Mohr DN, Fairbanks VF. Methemoglobinemia from topically applied anesthetic spray. Mayo Clin Proc 1994; 69:886-888
were generally benevolent to humans and were said to be the custodians of treasures hidden in the earth and in the roots of trees. The female yaksha, or yakshi, was often depicted as a heavily jeweled fertility figure. Chief among the yakshas was Kubera, who ruled the mythical Himalayan kingdom of Alaka and was associated with the earth, mountains, and all the treasures (such as minerals and jewels) that lay underground. He was guardian of the northern lands and was usually depicted as a potbellied dwarf holding a moneybag or pomegranate (the symbol of fertility). In art, sculptures of yakshas are among the earliest representations of deities. These ancient sculptures usually portray the yakshas as large, potbellied figures. The yaksha is depicted on this stamp issued by India in 1961.