Biographical Article
Douglas Van Anden Frost (1910-1989) J. E. OLDFIELD
called Factor W that had been conducted in his labo ratory. Frost's research soon showed it to be a mixture of water-soluble substances that were apparently needed for rapid growth of rats (1). His path led him to nicotinic acid, and, in those heady days of the golden age of nutrition, he wondered whether this might not be a member of the new found family of vitamins. Simon Black, a classmate of Frost's, now with the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health in Bethesda, MD, recalls some of the details, "He was impressed by die newly-established formulas for coenzymes I and n (the pyridine nucleotides) and conceived the idea that they might be vitamins. We jumped on him for that, saying that the coenzymes could never survive the cleavage reactions in extracts, whereupon Doug suggested that a cleavage product might work, one of them being nicotinic acid." Frost's first experiments in support of this line of reasoning, conducted on rats, were inconclusive, and he prevailed upon Bob Madden to let Him test nico tinic acid in dogs. After a search they found a moribund dog. Nicotinic acid was administered, and, as the story has it, the next morning the dog was up, pawing at the cage walls and barking at passers-by, so rapid was its recovery. This was a momentous dis covery and helped to abolish pellagra among the people of the South. Elvehjem promoted Dr. Frost, but sadly Frost's name did not appear on the famous paper (2). One can speculate on the influence that this early experiment had on Dr. Frost's later career. When Elvehjem was criticized for having missionary spirit in his talks about the importance of vitamins to human health, Frost rose to his defense, saying that he was merely repeating and interpreting what had been proven about vitamins through scientific experi mentation. This may well have led to Dr. Frost's own missionary zeal in later years, as far as the trace elements were concerned. It may have been no mere coincidence that he chose to work with two of the most toxic trace ele ments, arsenic and selenium. I remember, many years later, Dr. Frost showing a slide depicting an old bottle of nicotinic acid, bearing the skull and crossbones
Can one person be both a maverick and a scientist? Apparently so, according to many of Douglas Frost's friends. That Dr. Frost was a very keen and metic ulous scientist there is no doubt. He pursued the search for truth about the nutritional qualities of arsenic and selenium with great vigor and determina tion, painstakingly accumulating information, some of which was ultimately accepted. But many of his friends describe him, affectionately, as a maverick who delighted in championing unorthodox views. Perhaps he stated the case best himself, when he offered "Thoughts on My Life," for his entry in the 1974-75 edition of Who's Who in America: "Being a contrarian is not enough. One must look with ex treme care at all facets of prejudice, vs. what research can really show to be so. Dedication to the repeatable experiment and what it can prove unequivocally is the one way man can serve Nature and have Nature serve him." In his later years, Dr. Frost's interests and talents became so involved with the trace elements and espe cially with arsenic and selenium that many people did not remember his significant contributions in other areas. These began very early in his career when he was still a graduate student working for Conrad Elvehjem at the University of Wisconsin. Dr. Elvehjem assigned him to continue studies of the so0022-3166/92
$3.00 ©1992 American
Institute
of Nutrition.
Accepted 27 August 1991. J. Nutr. 405
122: 405-411,
1992.
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
Department of Animal Science, Oregon State University, Corvallis, OR 97331
406
OLDFffiLD
THE EARLY YEARS Douglas V. Frost was born in Pittsburgh, PA, on October 31, 1910. He spent his preschool and elementary school years in Schenectady, NY, where his father worked for the General Electric Company. About 1926 or early 1927 the family moved to Rockford, IL, where Mr. Frost was employed by a thriving machinery company. Douglas and his brother Craig entered Rockford High School in 1927. A friend, Charles Mellen, recalls some details of the high school scene at that time: "Doug and I both played the clarinet and sat next to each other in the band. We would often talk about things after school—serious things about the world and scientific wonders of the time—and what we wanted to do after graduating from high school and, perhaps, college. I was not sure what I wanted to do, but Douglas always knew exactly what he wanted. "Being in the high school band meant we were often called upon to march and play in parades, which were big in those days in Rockford, and we became good friends. Doug joined the track team at school and won a letter in bis senior year, although we were not supposed to be in the band and athletics at the same time. We also played golf and tennis together and he was very competitive. He had a great sense of humor and could see the funny side of situations that I could not." The two young men proceeded to undergraduate programs at the University of Illinois, where Frost received a B.A. in chemistry in 1933. Again there was evidence of his sense of purpose and determination. In the depths of the Great Depres sion, when many students took whatever job they could find, Frost decided to continue his education at the University of Wisconsin, where he earned his M.A. in 1938 and his Ph.D. in 1940, both in biochem istry. Right after graduation he married Muriel Louise (Mitzi) Newkirk, who was also from Schenectady, and the two of them made an outgoing and enduring team. The Frosts had four children: Nancy, Melodie, Roy and Constance.
THE ABBOTT YEARS In 1940 Dr. Frost joined the staff of Abbott Labora tories in Chicago where he was first assigned to study
the stability of B vitamins in various formulations for human use. He published several papers on the sta bility of tbi amine. Soon his work expanded to include development of conditions and procedures for hydrolyzing amino acids and for preparing lipid emul sions for parenteral nutrition. Within a few years he was promoted to head of Nutrition Research, a po sition he filled with distinction until his retirement from Abbott Laboratories in 1966. While at Abbott Laboratories Dr. Frost began to focus on the roles of trace elements in nutrition. These were days when the lack of sensitive analytical procedures hampered research with micronutrients and when the custom in texts covering the mineral elements was to categorize them as either essential or toxic. He was intrigued by the profound metabolic activity of some trace elements in eliciting toxic reac tions even at relatively low dietary levels, and rea soned that they might perform useful nutrient func tions even at lower systemic levels. The maverick side of his nature expressed itself in his first choice for study, arsenic, which the public probably con sidered the most deadly element. His involvement with animal nutrition had identified useful applica tions of arsenic, although they had not been estab lished on a scientific basis. Fowler's solution, a 1% aqueous solution of potassium arsenite, had been used for years by livestock producers as a general pick-me-up and a means of producing a healthy looking sheen on the coats of show Animáis. With perseverance and meticulous attention to de tail, Dr. Frost began to study the nutritional necessity of arsenic. He noted that arsenic in trace amounts stimulated phosphorylation; it was consistently found in living tissue and did not accumulate at tolerated levels (3). As he was to do later with selenium, he noted that there was really more evidence for arsenic as a protection against certain types of cancer than for arsenic as a carcinogen (4). He questioned why tars high in arsenic caused fewer cancers than tars low in arsenic, and he claimed that lead arsenate did not act as a carcinogen or cocarcinogen, although other lead salts did (5). Organic arsenicals are far less toxic than inorganic arsenite and arsenate, of course. Arsphenamine (salvarsan; Ehrlich's "magic bullet") is an example. Jukes and Welch (6) showed that arsenocholine could re place choline for growth and for prevention of perosis in chicks. Frost's interest in arsenic included the use of arsanilic acid to promote growth and as a coccidiostat for chickens. This originated in the finding by Morehouse and Mayfield (7) that the coccidiostat 3-nitro-4 hydroxyphenylarsonic acid increased the growth of chicks and turkeys when added to the diet. In contrast, inorganic arsenic is commonly regarded as a carcinogen. In 1950 Dr. Frost persuaded Abbott to market arsa nilic acid as a growth-stimulating feed additive for animals and poultry. Interestingly, in view of his earlier inquiries concerning relationships of arsenic to
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
poison symbol, when he wanted to make the point that, at different dosage levels, one and the same substance could be both an essential nutrient and a deadly poison. This was not true for nicotinic acid, however. Nicotinic acid is used for various purposes at very high dosages, and the skull and crossbones label may have been used only through ignorance, because the name "nicotinic" was reminiscent of nicotine.
DOUGLAS VAN ANDEN
407
his attention on selenium, and continued this interest for the rest of his career.
THE DARTMOUTH EPISODE As Dr. Frost approached retirement from Abbott Laboratories, he considered devoting himself full time to the study of the toxic microelements arsenic and selenium. A friend, Walter Mertz, of the Human Nutrition Research Center of the U.S. Department of Agriculture at Beltsville, MD, suggested that he join Henry Schroeder, who was then active in trace element research, at his Dartmouth laboratory. Dr. Frost went to Dr. Schroeder's headquarters in Brattleboro, VT, in 1966, with the objective of investigating whether very low concentrations of arsenic might prove essential for rats in long-term experiments. Before this could be accomplished the two men developed substantial disagreements over selenium, not arsenic. Schroeder was convinced that selenium was a carcinogen. Frost was equally sure it was not and the two argued over procedural issues in the laboratory. Frost was beginning to believe that selenium might, in some cases, be anticarcinogenic, based on some preliminary surveys Unking cancer incidence to environmental levels of selenium (9). The rift became so complete that Dr. Frost felt con strained to publicly withdraw his name from coauthorship of a paper with Dr. Schroeder (10). Shortly thereafter, Dr. Frost left the Dartmouth labo ratory and established himself as a consultant in nutrition and biochemistry in Schenectady, NY, and continued his efforts to establish and confirm the useful biological applications of arsenic and selenium.
THE SELENIUM STORY Although his busy life encompassed an impressive number of important areas of investigation, Dr. Frost is probably best known for his persistent search for factual data to support the nutritional and therapeutic qualities of selenium. It was coincidentally the least plentiful and the most toxic of the essential trace elements. He was intrigued, as he had been with arsenic, to discover whether selenium's great metabolic activity could be beneficial, at levels below its known toxic concentra tions. Certainly there were challenges enough for the scientist in him, and, in retrospect, the opportunity to oppose the considerable weight of opinion from people he termed "selenophobes," against any such benefits, may have appealed to his maverick side. Dr. Frost plotted his research strategy with care. First, selenium had to be proven, unequivocally, to be an essential nutrient. At this time he was working independently without laboratory facilities, and he
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
cancer, in long-term studies with graded levels of arsanihc acid, he was encouraged to find that the lowest levels of spontaneous cancer occurrence were in the animals consuming the highest level of arsa nilic acid feed (8). In the course of his studies with arsenic, Dr. Frost became convinced that the regulatory levels for per missible levels of arsenic in foods and water were unnecessarily low. The benchmark in establishing such levels in this country was the level set in Great Britain following what was referred to as the Beer Poisoning Epidemic in 1900, for which arsenic was blamed. He studied everything he could find about the disaster in Chicago's Crerar Library and con cluded that the evidence was equivocal and that ar senic could not logically be considered solely respon sible. The beer-poisoning epidemic caused some 1000 deaths and about 7000 became ill, so it created an emotional as well as medical crisis in England for which a solution was urgently needed. A royal com mission was appointed to study the situation and reported finding both arsenic and selenium in the beer and also in the brewing sugar and the sulfuric acid used to invert the sugar. Partly because the word "arsenic" was almost synonymous with the word "poison," Frost thought, the royal commission offered a popular solution and indicted arsenic, failing even to mention that arsenic and selenium in combination could have caused the tragedy (3). The commission pursued its charge to prevent a recurrence of such disasters by establishing a safe limit for arsenic in brewing sugars, in beers and in foods generally. The level of tolerance was set at 0.01 grain As/lb for solid foods and 0.01 grain/gal for beer. The former level is equivalent to 0.01 |ig/g, and this has been adopted in other countries. During this period Dr. Frost also visited and inves tigated various locations where environmental levels of arsenic were high and found no evidence for arsenic-induced cancer. In the Reparoa Valley, which is in the geothermal zone of New Zealand, soils contain up to 1.0% As, and pasture forage an average of 5.5 ng/g As. Except when animals ate significant quantities of the arsenical soil, there were no cases of arsenic toxicity, and the area was recognized as one of low cancer incidence. Similar absences of any in creased cancer occurrence was noted in high arsenic areas in Lowell, OR; Hanford, CA and Fallón,NV. Although Dr. Frost never succeeded in establishing arsenic as an essential nutrient to the extent that he desired, his painstaking search and careful interpre tation of the scientific literature did much to dispel the myths and untruths that surround this ubiquitous element. Perhaps because of its frequent associations with arsenic or perhaps because his maverick side recog nized a similarly demanding challenge from another, highly toxic element, Dr. Frost now focussed much of
FROST
408
OLDHELD
infamous Delaney Amendment to the Pure Food and Drug Law, Doug joined the battle in earnest. He very eloquently pointed out how Congress had gotten the legal niceties of absolutes entangled with the world of science, where absolute is more of a concept that you can never prove.'" These efforts certainly encouraged continuing research with selenium on a very broad scale. Dr. Frost's underlying conviction was that selenium, far from being a carcinogen, actually had anticarcinogenic properties, and he threw himself into investigations of this concept with his usual vigor and determination. His first survey linking cancer incidence and mortalities to environmental levels of selenium attracted world-wide discussion. Dr. Frost was well aware of the shortcomings of such surveys and the uncontrolled variables involved, but they were a starting point, and he quickly followed up with more definitive studies in which blood selenium levels in cancer patients were compared with those of healthy individuals under similar conditions. Others took up the challenge, and he was greatly encouraged to see his predictions of protective properties of selenium confirmed for several specific types of cancer (19). Biological research with selenium proceeded at a truly astonishing rate. There are several yardsticks that indicate this proliferation. The first edition of Underwood's classic text, Trace Elements in Human and Animal Nutrition devoted only a few pages to selenium, almost all of them describing its toxic prop erties. The third edition (published in 1971) had 39 pages on selenium, 29 of which related to its nutri tional value. The proceedings report for the First In ternational Conference on Selenium in Biomedicine, held in Corvallis, OR in 1966 was a volume of 445 pages,- that for the third such symposium, held in Beijing, China in 1984, was a two-volume set of 1138 pages. Dr. Frost's championing of the benign side of selenium's Jekyll-Hyde nature was an important factor in stimulating this research effort and in gener ating the funds to support it. He was a firm believer in the important of interchange of scientific infor mation and was active in arranging forums where this could take place. He served on the organizing com mittees for international conferences on uses of selenium that were held in Corvallis, OR; Lubbock, TX; South Bend, IN; Toronto, Canada,- Stockholm, Sweden and Banff, Canada. At several of these he was asked to give both opening and summary addresses and did so with his usual wit and wisdom, but he enjoyed himself most in informal discussions with participants. In the course of all these deliberations, Dr. Frost became convinced that the world might face a diminishing supply of selenium, which could have disastrous consequences. "The selenium cycle is winding down," he often remarked, and cited several reasons: the burning of fossil fuels reduced oxidized
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
did no research with selenium himself but accom plished his objectives by encouraging others to do the required studies, sometimes helping to defray the costs by grants arranged through the SeleniumTellurium Development Association, for which he was a consultant. He was delighted when evidence supporting useful functions for selenium began to accumulate: first the discovery that it prevented liver degeneration in rats (11) and exudative diathesis in chicks (12) and the almost-simultaneous disclosure in pigs by the Lederle group (13). These were followed by demonstration of its protective effects against white muscle disease in young ruminants (14) and its proven stimulation of reproductive performance in sheep (15), but he was even more encouraged by purified diet studies that clearly established its nu trient essentiality (16, 17). He was an active cor respondent with all these investigators and visited their laboratories whenever possible. He maintained correspondence with investigators all over the world, and many of his friends report picking up the phone at all hours of the night to hear the familiar voice, "This is Doug Frost. Have you seen So-and-so's work, in New Zealand (or Finland or China)," followed by a detailed interpretation of the results. Research never proceeded fast enough to suit him, and he figured that one way to accelerate it would be to gain some sort of official recognition of selenium's new status, to help free government funds that might not be available for work with a toxin. He became a hard-working member of the selenium subcommittee of the National Research Council's Committee on Animal Nutrition and played an important role in the publication of its report "Selenium in Nutrition," published by the National Academy Press in 1971. This publication was the data base from which the American Feed Industry Association prepared its pro posal for feed supplement status for selenium, which was approved by the Food and Drug Administration in 1974. This legitimized the use of selenium at phys iological levels, and stimulated a great many useful studies of selenium with domestic animals. Another major deterrent to broadened nutritional studies with selenium was the continuing suspicion of many that it was carcinogenic. Dr. Frost attacked this in two ways: he promoted a careful reexamination of the kind of graded Se-level rat feeding trials that had led to the original association between cancer and selenium in rats at the FDA laboratories. The new work was done at Oregon State University and clearly showed that selenium, at nutritional levels, was not a carcinogen (18). His second approach was to attack the Delaney Amendment to the Food, Drug and Cosmetic Act as unworkable. This was important, because, if selenium were labeled as a carcinogen, it would have been impossible to add it to animal feeds, at any level, under the Delaney amend ment. A friend, Irvin Smith, recalled this involve ment: "Once the controversy started over the now
DOUGLAS VAN ANDEN
SOME OTHER INVOLVEMENTS RECOGNITIONS
AND
There is no question that the search for the truth about selenium dominated Douglas Frost's time. Many friends were amazed by the volume of his worldwide correspondence through detailed letters he typed on an old manual typewriter. With all of this involvement, however, he still found time to work for incidental causes that he deemed important. One of these was the conversion of the United States to the use of the metric system. Louis Sokol, President Emeritus of the U.S. Metric Association, recalls "Doug was an ardent supporter of metrification and during the late 1960s testified before a Congressional committee in support of the issue and pending legis lation to enact the Metric Study Bill, which passed in 1968." Dr. Frost was president of the Metric Associ ation from 1969-1980. He was active in a number of professional societies, including the American Chemical Society, the American Institute of Nutrition (Editorial Board, 1959-1963, Fellow, 1988), Association of Vitamin Chemists (President, 1959), New York Academy of Sciences (Fellow, 1952), Animal Nutrition Research Council (Chairman, 1959-1960) and the Nutrition Council of the American Feed Manufacturers' Association (1953-1956). Never one to seek honors, he was never theless recognized for his dedication to the study of selenium by the Friedrich Schiller medal, given jointly by the University of Jena, Germany, and Karl Marx University of Leipzig, Germany, in 1983 and by the Klaus Schwarz memorial medal in 1988.
PERSONAL
409
provide these. Ernest Volwiler, former chief executive officer at Abbott Laboratories, described Frost's deter mination as being like "David facing Goliath, as he moved against the forces who were certain that no trace of arsenic or selenium must ever be found in the food of man or animal." Thomas Jukes of the Uni versity of California, Berkeley, who knew him well, shared similar thoughts: "Doug was never dis couraged about [his convictions concerning] arsenic and selenium. He fought bad health and never stopped pushing." Herbert Boynton, of Nutrition 21 in San Diego, recalls, "It was Doug who first pointed out the many subtle factors, e.g., acid rain, over grazing, food refining, that can and do lead to alarming reductions in the selenium content of our food supply." Manfred Anke, from the Friedrich Schiller University wrote of the international implica tions of his work: "He helped us a lot and always understood our symposia in Jena as a possibility of maintaining contact between scientists in the East and West." Mark Hegsted from Harvard Medical School noted his preoccupation with the trace ele ments, "When Doug had his by-pass [operation] at the Brigham [hospital], I went over to see him soon after. He was barely out of the anesthesia but he looked up and began to tell me that latest stuff about arsenic and selenium." We must remember that, with all this intense pro fessional activity, Dr. Frost was at the same time a warm and fun-loving human being. The Frosts had a beautiful summer place at Lake George in upstate New York where they frequently entertained friends. Charles Cooper, of Noranda Mines, who chaired the Selenium-Tellurium Development Association, wrote of a visit there: "On our arrival, a few steps from the wharf, our young son heard a hissing sound, and there, near his feet, was a rattler! It was promptly disposed of and Doug took the rattle to the county office in Bolton Landing to collect the bounty. Next Christmas, along with the Christmas card from Doug and Mitzi, was a check for $5 for our son, this being the bounty Doug had received." Among other com ments, Ralph Zingaro of Texas A & M University concluded, "He was always very reasonable and tol erant and not dogmatic about presenting his point of view ... he represented a rare breed, viz. he was a nice person." And his schoolmate and lifelong friend, Floyd Mclntire summed up their association, "He was a very special and loyal friend."
REFLECTION
It is difficult to capture in a few, short pages the essence of a life that was filled with so much pur poseful activity. It is easy to list accomplishments and events, but these are statistics that need fleshing out with personal recollections. Many of Douglas Frost's friends and associates have been pleased to
NOTE BY BIOGRAPHICAL
EDITOR
Doug Frost's contribution to the identification of nicotinic acid as the anti-black tongue factor (antipellagra factor) is best told in his own unvarnished words as written in a letter to me March 28, 1980.
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
forms of elemental selenium, which is biologically unavailable; oxides of sulfur and nitrogen lowered soil pH, facilitating binding of selenium to various metals and fertilization of soils with nitrogen, sulfur and perhaps phosphates depressed selenium uptake by plants, as did the reduction of selenium to elemental form in the excreta of grazing animals. He perceived ways that this potential problem could be avoided and if he had not been an environmentalist before, he now became one and spoke out strongly against acid rain. It will be interesting to see whether his prescience about this issue matches the accuracy of some of his earlier predictions about this interesting element.
FROST
410
OLDFEELD
Doug was evidently overawed by Elvehjem, and felt adequately compensated for being excluded from the blacktongue discovery publication by being given a "prime" job after being "convinced" that his role had been "too prominent." Frost's idea of testing the liver concentrate for stability to boiling with acid and alkali was a stroke of inspiration, and surely he should receive more credit for the fact that nicotinic acid (bowdlerized to niacin on bread wrappers) re moved the scourge of pellagra from the southeastern USA, and elsewhere, in the late 1930s. His colleagues, Esmond Snell and Wayne Woolley, joined in urging Madden to test nicotinic acid (21). His ideas about arsenic, on the other hand, I have always found difficult to accept. Richard Doll lists arsenic as increasing both the occupational and iatrogenic incidence of skin and lung cancer, and S. Hornberg says that arsenic "has been connected with an excess of skin and lung cancer" and "in some studies with cancer of the lymphatic system and hemangiosarcoma of the liver" (22). Frost, in his extensive review of the "beer catas trophe" (3), attributed the deaths of 1000 people to selenium rather than arsenic. He does not cite the levels of selenium found in the beer, and this makes interpretation difficult, but he says that "the unusual and bizarre symptoms" described for the victims "resemble symptoms assigned decades later to selenium toxicity in humans." He also says that "an excessive level of As may accentuate, rather than
decrease, Se toxicity," citing work with chickens. Frost was interested in the effects of selenium, but apparently not in the role of selenocysteine. See the review by T. Stadtman (23). Thomas H. Jukes
ACKNOWLEDGMENTS Many people have contributed to this brief biog raphy, and their affection and respect for the subject has been heartwarming. Among others, special thanks are due to members of Dr. Frost's family, Muriel (Mitzi) Frost and Melodie Cooey, and to the fol lowing: Manfred Anke; Jack Bauernfeind; Simon Black; Herbert Boynton,- Sam Carapella,- Charles Cooper; Mark Hegsted; Thomas Jukes,- Floyd Mclntyre; Charles Mellen,- Walter Mertz; Olaf Mickelsen,Bernard Schermetzler,- Irvin Smith; Louis Sokol; Chris Stater,- Sally Swift; Ernest Volwiler; Harold Zaugg and Ralph Zingaro.
LITERATURE CITED 1. Frost, D. V. &.Elvehjem, C. A. (1939)Factor W and its relation to the vitamin B complex. J. Biol. Chem. 128: 23-29. 2. Elvehjem, C. A., Madden, R., Strong, F. M. A. Woolley, D. W. (1937) Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J. Am. Chem. Soc. 59: 1767-1768. 3. Frost, D. V. (1967) Arsenicals in biology—retrospect and pros pect. Fed. Proc. 26: 194-208. 4. Frost, D. V. (1980)The two faces of arsenic—can arsenophobia be cured? In: Arsen 3. Spurunelement Symposium, pp. 17-23. Karl Marx University, Leipzig, Germany, and Friedrich Schiller University, Jena, Germany. 5. Kroes, R., VanLogten, M. J., Berkovens, J. M., de Vries, T. fil van Eoch, C. J. (1974) Study of the carcinogenicity of lead arsenale and sodium arsenale and the possible syncrgistic effect of dimethylnitrosarnine. Food Cosmet. Toxicol. 12: 671-679. 6. Jukes, T. H. &. Welch, A. D. (1942) The effects of certain analogs of choline on perosis. J. Biol. Chem. 146: 19-24. 7. Morehouse, N. F. & Mayfield, O. J. (1946) The effect of some aryl arsonic acids on coccidiosis infection in chickens. J. Parasitol. 32: 20-24. 8. Frost, D. V. (1960)Arsenic and selenium in relation to the food additive law of 1958. Nutr. Rev. 18: 129-132. 9. Shamberger, R. J. &. Frost, D. V. (1969) Possible protective effect of selenium against human cancer. Can. Med. Assoc. J. 100: 682-683. 10. Frost, D. V. (1972) Regarding the paper 'Essential trace metals: selenium' by Schroeder, H. A., D. V. Frost and J. J. Salassa (Letter to the Editor). J. Chronic Dis. 25: MS397. 11. Schwarz, K. &.Foltz, C. M. (1957) Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration. J. Am. Chem. Soc. 79: 3292-^2,93. 12. Patterson, E. L., Milstrey, R. & Stokstad, E.L.R. (1957)Effect of selenium in preventing exudative diathesis in chicks. Proc. Soc. Exp. Biol. Med. 95: 617-ÄW. 13. Eggert, R. O., Patterson, E., Akers, W. J. &. Stokstad, E.L.R. (1957)The role of vitamin E and selenium in the nutrition of the pig. J. Anim. Sci. 16: 1037-1042. 14. Muri, O. H., Oldfield, J. E., Remmert, L. R. &. Schubert, J. R. (1958) Effects of selenium and vitamin E on white muscle disease. Science (Washington, DC) 128: 1090. 15. Hartley, W. J., Grant, A. B. &. Drake, C. (1960) Control of
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
My findings [slight growth responses in rats to nicotinic acid, nicotinamide and adenine nucleotide, reported by Frost and Elvchjcm (2)],plus Knight's discovery of nicotinamide as a growth factor for Staph. auieus, plus knowledge of the great stability of nicotinic acid to acid and alkali made me certain that nicotinic acid should be tested in dogs. I had urged Bob Madden to boil up Carl Koehn's water white concentrate from liver that cured blacktongue, first with acid and next with alkali. Bob used my ground glass equipment for both and we had to break the one he used with NaOH to get the joints apart. He told me that both cured blacktongue after neutralization. In all fairness, Tom, Connie Elvehjem was not impressed and Madden fed nicotinic acid after my strong urging. Connie was very busy with more than 30 grad students and none of us had much time with him. The FrostElvehjem paper was received for publication 8/5/37 and the discovery letter by Elvehjem and co-workers (2) came more than a month later. In the Elvehjem, Madden, Strong, Woolley (20) paper, much of my literature review of the relation of nicotinamide to coenzyme and cozymase is used verbatim. I became convinced that my role had been too prominent and being offered the prime job as Connie's teaching assistant was automatically shifted to research with Hart and Elvehjem on the copper, iron research, which tradi tionally went with that job. I made it research with Cu, Fe and Co and just kept on working harder than ever. It so happened my folks invited me to help them drive to Yel lowstone in August, 1937. When we got back to Madison, Connie had already sent in his letter to the JACS and I was off the B-Complex research completely. I did more literature research tracing Casimir Funk's failure to place just where N.A. fit in the B-complex, but was soon far too busy with other research and teaching to do much else. I was extremely beholden to Connie for giving me the chance to serve as a grad student and realized how much the breakthrough would mean to him
DOUGLAS VAN ANDEN
16.
17.
19.
20.
21. 22.
23.
411
Zenobiotic Metabolism: Nutritional Effects. (Finley, J. W. & Schwärs,D. E., eds.) pp. 267-282. American Chemical Society Symposium Series 277, Washington, DC. Elvehjem, C. A., Madden, R. J., Strong, F. M. & Woolley, D. W. (1938) The isolation and identification of the anti-black tongue factor. J. Biol. Chem. 123: 137-149. Jukes, T. H. (1974) Dilworth Wayne Woolley. J. Nutr. 104: 509-511. Hiatt, H. H., Watson, J. D. &. Winsten, J. A (1977) Origins of Human Cancer. Book A, pp 2-4, 147-148. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Stadtman, T. (1990) Selenium biochemistry. Annu. Rev. Biochem. 59: 111-127.
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
18.
white muscle disease and ill-thrift with selenium. N. Z. J. Agrie. Res. 101: 343-347. Scott, M. L. & Thompson, J. N. (1968) Selenium in nutrition and metabolism, pp. 1-10. In: Proceedings of the Maryland Conference for Feed Manufacturers, College Park, MD. McCoy, K.E.M. &. Weswig, P. H. (1969) Some selenium responses in the rat not related to vitamin E. J. Nutr. 98: 383-389. Harr, J. R., Bone, J. F., Tinsley, I. J., Weswig, P. H. &. Yamamoto, R. W. (1967) Selenium toxicity in rats. H. Histopathology. In: Symposium: Selenium in Biomedicine, pp. 153-178. Avi Publishing, Westport, CT. Mimer, J. A. (1985) Selenium and carcinogenesis. In:
FROST
Douglas Van Anden Frost (1910-1989) J. E. OLDFIELD
called Factor W that had been conducted in his labo ratory. Frost's research soon showed it to be a mixture of water-soluble substances that were apparently needed for rapid growth of rats (1). His path led him to nicotinic acid, and, in those heady days of the golden age of nutrition, he wondered whether this might not be a member of the new found family of vitamins. Simon Black, a classmate of Frost's, now with the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health in Bethesda, MD, recalls some of the details, "He was impressed by die newly-established formulas for coenzymes I and n (the pyridine nucleotides) and conceived the idea that they might be vitamins. We jumped on him for that, saying that the coenzymes could never survive the cleavage reactions in extracts, whereupon Doug suggested that a cleavage product might work, one of them being nicotinic acid." Frost's first experiments in support of this line of reasoning, conducted on rats, were inconclusive, and he prevailed upon Bob Madden to let Him test nico tinic acid in dogs. After a search they found a moribund dog. Nicotinic acid was administered, and, as the story has it, the next morning the dog was up, pawing at the cage walls and barking at passers-by, so rapid was its recovery. This was a momentous dis covery and helped to abolish pellagra among the people of the South. Elvehjem promoted Dr. Frost, but sadly Frost's name did not appear on the famous paper (2). One can speculate on the influence that this early experiment had on Dr. Frost's later career. When Elvehjem was criticized for having missionary spirit in his talks about the importance of vitamins to human health, Frost rose to his defense, saying that he was merely repeating and interpreting what had been proven about vitamins through scientific experi mentation. This may well have led to Dr. Frost's own missionary zeal in later years, as far as the trace elements were concerned. It may have been no mere coincidence that he chose to work with two of the most toxic trace ele ments, arsenic and selenium. I remember, many years later, Dr. Frost showing a slide depicting an old bottle of nicotinic acid, bearing the skull and crossbones
Can one person be both a maverick and a scientist? Apparently so, according to many of Douglas Frost's friends. That Dr. Frost was a very keen and metic ulous scientist there is no doubt. He pursued the search for truth about the nutritional qualities of arsenic and selenium with great vigor and determina tion, painstakingly accumulating information, some of which was ultimately accepted. But many of his friends describe him, affectionately, as a maverick who delighted in championing unorthodox views. Perhaps he stated the case best himself, when he offered "Thoughts on My Life," for his entry in the 1974-75 edition of Who's Who in America: "Being a contrarian is not enough. One must look with ex treme care at all facets of prejudice, vs. what research can really show to be so. Dedication to the repeatable experiment and what it can prove unequivocally is the one way man can serve Nature and have Nature serve him." In his later years, Dr. Frost's interests and talents became so involved with the trace elements and espe cially with arsenic and selenium that many people did not remember his significant contributions in other areas. These began very early in his career when he was still a graduate student working for Conrad Elvehjem at the University of Wisconsin. Dr. Elvehjem assigned him to continue studies of the so0022-3166/92
$3.00 ©1992 American
Institute
of Nutrition.
Accepted 27 August 1991. J. Nutr. 405
122: 405-411,
1992.
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
Department of Animal Science, Oregon State University, Corvallis, OR 97331
406
OLDFffiLD
THE EARLY YEARS Douglas V. Frost was born in Pittsburgh, PA, on October 31, 1910. He spent his preschool and elementary school years in Schenectady, NY, where his father worked for the General Electric Company. About 1926 or early 1927 the family moved to Rockford, IL, where Mr. Frost was employed by a thriving machinery company. Douglas and his brother Craig entered Rockford High School in 1927. A friend, Charles Mellen, recalls some details of the high school scene at that time: "Doug and I both played the clarinet and sat next to each other in the band. We would often talk about things after school—serious things about the world and scientific wonders of the time—and what we wanted to do after graduating from high school and, perhaps, college. I was not sure what I wanted to do, but Douglas always knew exactly what he wanted. "Being in the high school band meant we were often called upon to march and play in parades, which were big in those days in Rockford, and we became good friends. Doug joined the track team at school and won a letter in bis senior year, although we were not supposed to be in the band and athletics at the same time. We also played golf and tennis together and he was very competitive. He had a great sense of humor and could see the funny side of situations that I could not." The two young men proceeded to undergraduate programs at the University of Illinois, where Frost received a B.A. in chemistry in 1933. Again there was evidence of his sense of purpose and determination. In the depths of the Great Depres sion, when many students took whatever job they could find, Frost decided to continue his education at the University of Wisconsin, where he earned his M.A. in 1938 and his Ph.D. in 1940, both in biochem istry. Right after graduation he married Muriel Louise (Mitzi) Newkirk, who was also from Schenectady, and the two of them made an outgoing and enduring team. The Frosts had four children: Nancy, Melodie, Roy and Constance.
THE ABBOTT YEARS In 1940 Dr. Frost joined the staff of Abbott Labora tories in Chicago where he was first assigned to study
the stability of B vitamins in various formulations for human use. He published several papers on the sta bility of tbi amine. Soon his work expanded to include development of conditions and procedures for hydrolyzing amino acids and for preparing lipid emul sions for parenteral nutrition. Within a few years he was promoted to head of Nutrition Research, a po sition he filled with distinction until his retirement from Abbott Laboratories in 1966. While at Abbott Laboratories Dr. Frost began to focus on the roles of trace elements in nutrition. These were days when the lack of sensitive analytical procedures hampered research with micronutrients and when the custom in texts covering the mineral elements was to categorize them as either essential or toxic. He was intrigued by the profound metabolic activity of some trace elements in eliciting toxic reac tions even at relatively low dietary levels, and rea soned that they might perform useful nutrient func tions even at lower systemic levels. The maverick side of his nature expressed itself in his first choice for study, arsenic, which the public probably con sidered the most deadly element. His involvement with animal nutrition had identified useful applica tions of arsenic, although they had not been estab lished on a scientific basis. Fowler's solution, a 1% aqueous solution of potassium arsenite, had been used for years by livestock producers as a general pick-me-up and a means of producing a healthy looking sheen on the coats of show Animáis. With perseverance and meticulous attention to de tail, Dr. Frost began to study the nutritional necessity of arsenic. He noted that arsenic in trace amounts stimulated phosphorylation; it was consistently found in living tissue and did not accumulate at tolerated levels (3). As he was to do later with selenium, he noted that there was really more evidence for arsenic as a protection against certain types of cancer than for arsenic as a carcinogen (4). He questioned why tars high in arsenic caused fewer cancers than tars low in arsenic, and he claimed that lead arsenate did not act as a carcinogen or cocarcinogen, although other lead salts did (5). Organic arsenicals are far less toxic than inorganic arsenite and arsenate, of course. Arsphenamine (salvarsan; Ehrlich's "magic bullet") is an example. Jukes and Welch (6) showed that arsenocholine could re place choline for growth and for prevention of perosis in chicks. Frost's interest in arsenic included the use of arsanilic acid to promote growth and as a coccidiostat for chickens. This originated in the finding by Morehouse and Mayfield (7) that the coccidiostat 3-nitro-4 hydroxyphenylarsonic acid increased the growth of chicks and turkeys when added to the diet. In contrast, inorganic arsenic is commonly regarded as a carcinogen. In 1950 Dr. Frost persuaded Abbott to market arsa nilic acid as a growth-stimulating feed additive for animals and poultry. Interestingly, in view of his earlier inquiries concerning relationships of arsenic to
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
poison symbol, when he wanted to make the point that, at different dosage levels, one and the same substance could be both an essential nutrient and a deadly poison. This was not true for nicotinic acid, however. Nicotinic acid is used for various purposes at very high dosages, and the skull and crossbones label may have been used only through ignorance, because the name "nicotinic" was reminiscent of nicotine.
DOUGLAS VAN ANDEN
407
his attention on selenium, and continued this interest for the rest of his career.
THE DARTMOUTH EPISODE As Dr. Frost approached retirement from Abbott Laboratories, he considered devoting himself full time to the study of the toxic microelements arsenic and selenium. A friend, Walter Mertz, of the Human Nutrition Research Center of the U.S. Department of Agriculture at Beltsville, MD, suggested that he join Henry Schroeder, who was then active in trace element research, at his Dartmouth laboratory. Dr. Frost went to Dr. Schroeder's headquarters in Brattleboro, VT, in 1966, with the objective of investigating whether very low concentrations of arsenic might prove essential for rats in long-term experiments. Before this could be accomplished the two men developed substantial disagreements over selenium, not arsenic. Schroeder was convinced that selenium was a carcinogen. Frost was equally sure it was not and the two argued over procedural issues in the laboratory. Frost was beginning to believe that selenium might, in some cases, be anticarcinogenic, based on some preliminary surveys Unking cancer incidence to environmental levels of selenium (9). The rift became so complete that Dr. Frost felt con strained to publicly withdraw his name from coauthorship of a paper with Dr. Schroeder (10). Shortly thereafter, Dr. Frost left the Dartmouth labo ratory and established himself as a consultant in nutrition and biochemistry in Schenectady, NY, and continued his efforts to establish and confirm the useful biological applications of arsenic and selenium.
THE SELENIUM STORY Although his busy life encompassed an impressive number of important areas of investigation, Dr. Frost is probably best known for his persistent search for factual data to support the nutritional and therapeutic qualities of selenium. It was coincidentally the least plentiful and the most toxic of the essential trace elements. He was intrigued, as he had been with arsenic, to discover whether selenium's great metabolic activity could be beneficial, at levels below its known toxic concentra tions. Certainly there were challenges enough for the scientist in him, and, in retrospect, the opportunity to oppose the considerable weight of opinion from people he termed "selenophobes," against any such benefits, may have appealed to his maverick side. Dr. Frost plotted his research strategy with care. First, selenium had to be proven, unequivocally, to be an essential nutrient. At this time he was working independently without laboratory facilities, and he
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
cancer, in long-term studies with graded levels of arsanihc acid, he was encouraged to find that the lowest levels of spontaneous cancer occurrence were in the animals consuming the highest level of arsa nilic acid feed (8). In the course of his studies with arsenic, Dr. Frost became convinced that the regulatory levels for per missible levels of arsenic in foods and water were unnecessarily low. The benchmark in establishing such levels in this country was the level set in Great Britain following what was referred to as the Beer Poisoning Epidemic in 1900, for which arsenic was blamed. He studied everything he could find about the disaster in Chicago's Crerar Library and con cluded that the evidence was equivocal and that ar senic could not logically be considered solely respon sible. The beer-poisoning epidemic caused some 1000 deaths and about 7000 became ill, so it created an emotional as well as medical crisis in England for which a solution was urgently needed. A royal com mission was appointed to study the situation and reported finding both arsenic and selenium in the beer and also in the brewing sugar and the sulfuric acid used to invert the sugar. Partly because the word "arsenic" was almost synonymous with the word "poison," Frost thought, the royal commission offered a popular solution and indicted arsenic, failing even to mention that arsenic and selenium in combination could have caused the tragedy (3). The commission pursued its charge to prevent a recurrence of such disasters by establishing a safe limit for arsenic in brewing sugars, in beers and in foods generally. The level of tolerance was set at 0.01 grain As/lb for solid foods and 0.01 grain/gal for beer. The former level is equivalent to 0.01 |ig/g, and this has been adopted in other countries. During this period Dr. Frost also visited and inves tigated various locations where environmental levels of arsenic were high and found no evidence for arsenic-induced cancer. In the Reparoa Valley, which is in the geothermal zone of New Zealand, soils contain up to 1.0% As, and pasture forage an average of 5.5 ng/g As. Except when animals ate significant quantities of the arsenical soil, there were no cases of arsenic toxicity, and the area was recognized as one of low cancer incidence. Similar absences of any in creased cancer occurrence was noted in high arsenic areas in Lowell, OR; Hanford, CA and Fallón,NV. Although Dr. Frost never succeeded in establishing arsenic as an essential nutrient to the extent that he desired, his painstaking search and careful interpre tation of the scientific literature did much to dispel the myths and untruths that surround this ubiquitous element. Perhaps because of its frequent associations with arsenic or perhaps because his maverick side recog nized a similarly demanding challenge from another, highly toxic element, Dr. Frost now focussed much of
FROST
408
OLDHELD
infamous Delaney Amendment to the Pure Food and Drug Law, Doug joined the battle in earnest. He very eloquently pointed out how Congress had gotten the legal niceties of absolutes entangled with the world of science, where absolute is more of a concept that you can never prove.'" These efforts certainly encouraged continuing research with selenium on a very broad scale. Dr. Frost's underlying conviction was that selenium, far from being a carcinogen, actually had anticarcinogenic properties, and he threw himself into investigations of this concept with his usual vigor and determination. His first survey linking cancer incidence and mortalities to environmental levels of selenium attracted world-wide discussion. Dr. Frost was well aware of the shortcomings of such surveys and the uncontrolled variables involved, but they were a starting point, and he quickly followed up with more definitive studies in which blood selenium levels in cancer patients were compared with those of healthy individuals under similar conditions. Others took up the challenge, and he was greatly encouraged to see his predictions of protective properties of selenium confirmed for several specific types of cancer (19). Biological research with selenium proceeded at a truly astonishing rate. There are several yardsticks that indicate this proliferation. The first edition of Underwood's classic text, Trace Elements in Human and Animal Nutrition devoted only a few pages to selenium, almost all of them describing its toxic prop erties. The third edition (published in 1971) had 39 pages on selenium, 29 of which related to its nutri tional value. The proceedings report for the First In ternational Conference on Selenium in Biomedicine, held in Corvallis, OR in 1966 was a volume of 445 pages,- that for the third such symposium, held in Beijing, China in 1984, was a two-volume set of 1138 pages. Dr. Frost's championing of the benign side of selenium's Jekyll-Hyde nature was an important factor in stimulating this research effort and in gener ating the funds to support it. He was a firm believer in the important of interchange of scientific infor mation and was active in arranging forums where this could take place. He served on the organizing com mittees for international conferences on uses of selenium that were held in Corvallis, OR; Lubbock, TX; South Bend, IN; Toronto, Canada,- Stockholm, Sweden and Banff, Canada. At several of these he was asked to give both opening and summary addresses and did so with his usual wit and wisdom, but he enjoyed himself most in informal discussions with participants. In the course of all these deliberations, Dr. Frost became convinced that the world might face a diminishing supply of selenium, which could have disastrous consequences. "The selenium cycle is winding down," he often remarked, and cited several reasons: the burning of fossil fuels reduced oxidized
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
did no research with selenium himself but accom plished his objectives by encouraging others to do the required studies, sometimes helping to defray the costs by grants arranged through the SeleniumTellurium Development Association, for which he was a consultant. He was delighted when evidence supporting useful functions for selenium began to accumulate: first the discovery that it prevented liver degeneration in rats (11) and exudative diathesis in chicks (12) and the almost-simultaneous disclosure in pigs by the Lederle group (13). These were followed by demonstration of its protective effects against white muscle disease in young ruminants (14) and its proven stimulation of reproductive performance in sheep (15), but he was even more encouraged by purified diet studies that clearly established its nu trient essentiality (16, 17). He was an active cor respondent with all these investigators and visited their laboratories whenever possible. He maintained correspondence with investigators all over the world, and many of his friends report picking up the phone at all hours of the night to hear the familiar voice, "This is Doug Frost. Have you seen So-and-so's work, in New Zealand (or Finland or China)," followed by a detailed interpretation of the results. Research never proceeded fast enough to suit him, and he figured that one way to accelerate it would be to gain some sort of official recognition of selenium's new status, to help free government funds that might not be available for work with a toxin. He became a hard-working member of the selenium subcommittee of the National Research Council's Committee on Animal Nutrition and played an important role in the publication of its report "Selenium in Nutrition," published by the National Academy Press in 1971. This publication was the data base from which the American Feed Industry Association prepared its pro posal for feed supplement status for selenium, which was approved by the Food and Drug Administration in 1974. This legitimized the use of selenium at phys iological levels, and stimulated a great many useful studies of selenium with domestic animals. Another major deterrent to broadened nutritional studies with selenium was the continuing suspicion of many that it was carcinogenic. Dr. Frost attacked this in two ways: he promoted a careful reexamination of the kind of graded Se-level rat feeding trials that had led to the original association between cancer and selenium in rats at the FDA laboratories. The new work was done at Oregon State University and clearly showed that selenium, at nutritional levels, was not a carcinogen (18). His second approach was to attack the Delaney Amendment to the Food, Drug and Cosmetic Act as unworkable. This was important, because, if selenium were labeled as a carcinogen, it would have been impossible to add it to animal feeds, at any level, under the Delaney amend ment. A friend, Irvin Smith, recalled this involve ment: "Once the controversy started over the now
DOUGLAS VAN ANDEN
SOME OTHER INVOLVEMENTS RECOGNITIONS
AND
There is no question that the search for the truth about selenium dominated Douglas Frost's time. Many friends were amazed by the volume of his worldwide correspondence through detailed letters he typed on an old manual typewriter. With all of this involvement, however, he still found time to work for incidental causes that he deemed important. One of these was the conversion of the United States to the use of the metric system. Louis Sokol, President Emeritus of the U.S. Metric Association, recalls "Doug was an ardent supporter of metrification and during the late 1960s testified before a Congressional committee in support of the issue and pending legis lation to enact the Metric Study Bill, which passed in 1968." Dr. Frost was president of the Metric Associ ation from 1969-1980. He was active in a number of professional societies, including the American Chemical Society, the American Institute of Nutrition (Editorial Board, 1959-1963, Fellow, 1988), Association of Vitamin Chemists (President, 1959), New York Academy of Sciences (Fellow, 1952), Animal Nutrition Research Council (Chairman, 1959-1960) and the Nutrition Council of the American Feed Manufacturers' Association (1953-1956). Never one to seek honors, he was never theless recognized for his dedication to the study of selenium by the Friedrich Schiller medal, given jointly by the University of Jena, Germany, and Karl Marx University of Leipzig, Germany, in 1983 and by the Klaus Schwarz memorial medal in 1988.
PERSONAL
409
provide these. Ernest Volwiler, former chief executive officer at Abbott Laboratories, described Frost's deter mination as being like "David facing Goliath, as he moved against the forces who were certain that no trace of arsenic or selenium must ever be found in the food of man or animal." Thomas Jukes of the Uni versity of California, Berkeley, who knew him well, shared similar thoughts: "Doug was never dis couraged about [his convictions concerning] arsenic and selenium. He fought bad health and never stopped pushing." Herbert Boynton, of Nutrition 21 in San Diego, recalls, "It was Doug who first pointed out the many subtle factors, e.g., acid rain, over grazing, food refining, that can and do lead to alarming reductions in the selenium content of our food supply." Manfred Anke, from the Friedrich Schiller University wrote of the international implica tions of his work: "He helped us a lot and always understood our symposia in Jena as a possibility of maintaining contact between scientists in the East and West." Mark Hegsted from Harvard Medical School noted his preoccupation with the trace ele ments, "When Doug had his by-pass [operation] at the Brigham [hospital], I went over to see him soon after. He was barely out of the anesthesia but he looked up and began to tell me that latest stuff about arsenic and selenium." We must remember that, with all this intense pro fessional activity, Dr. Frost was at the same time a warm and fun-loving human being. The Frosts had a beautiful summer place at Lake George in upstate New York where they frequently entertained friends. Charles Cooper, of Noranda Mines, who chaired the Selenium-Tellurium Development Association, wrote of a visit there: "On our arrival, a few steps from the wharf, our young son heard a hissing sound, and there, near his feet, was a rattler! It was promptly disposed of and Doug took the rattle to the county office in Bolton Landing to collect the bounty. Next Christmas, along with the Christmas card from Doug and Mitzi, was a check for $5 for our son, this being the bounty Doug had received." Among other com ments, Ralph Zingaro of Texas A & M University concluded, "He was always very reasonable and tol erant and not dogmatic about presenting his point of view ... he represented a rare breed, viz. he was a nice person." And his schoolmate and lifelong friend, Floyd Mclntire summed up their association, "He was a very special and loyal friend."
REFLECTION
It is difficult to capture in a few, short pages the essence of a life that was filled with so much pur poseful activity. It is easy to list accomplishments and events, but these are statistics that need fleshing out with personal recollections. Many of Douglas Frost's friends and associates have been pleased to
NOTE BY BIOGRAPHICAL
EDITOR
Doug Frost's contribution to the identification of nicotinic acid as the anti-black tongue factor (antipellagra factor) is best told in his own unvarnished words as written in a letter to me March 28, 1980.
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
forms of elemental selenium, which is biologically unavailable; oxides of sulfur and nitrogen lowered soil pH, facilitating binding of selenium to various metals and fertilization of soils with nitrogen, sulfur and perhaps phosphates depressed selenium uptake by plants, as did the reduction of selenium to elemental form in the excreta of grazing animals. He perceived ways that this potential problem could be avoided and if he had not been an environmentalist before, he now became one and spoke out strongly against acid rain. It will be interesting to see whether his prescience about this issue matches the accuracy of some of his earlier predictions about this interesting element.
FROST
410
OLDFEELD
Doug was evidently overawed by Elvehjem, and felt adequately compensated for being excluded from the blacktongue discovery publication by being given a "prime" job after being "convinced" that his role had been "too prominent." Frost's idea of testing the liver concentrate for stability to boiling with acid and alkali was a stroke of inspiration, and surely he should receive more credit for the fact that nicotinic acid (bowdlerized to niacin on bread wrappers) re moved the scourge of pellagra from the southeastern USA, and elsewhere, in the late 1930s. His colleagues, Esmond Snell and Wayne Woolley, joined in urging Madden to test nicotinic acid (21). His ideas about arsenic, on the other hand, I have always found difficult to accept. Richard Doll lists arsenic as increasing both the occupational and iatrogenic incidence of skin and lung cancer, and S. Hornberg says that arsenic "has been connected with an excess of skin and lung cancer" and "in some studies with cancer of the lymphatic system and hemangiosarcoma of the liver" (22). Frost, in his extensive review of the "beer catas trophe" (3), attributed the deaths of 1000 people to selenium rather than arsenic. He does not cite the levels of selenium found in the beer, and this makes interpretation difficult, but he says that "the unusual and bizarre symptoms" described for the victims "resemble symptoms assigned decades later to selenium toxicity in humans." He also says that "an excessive level of As may accentuate, rather than
decrease, Se toxicity," citing work with chickens. Frost was interested in the effects of selenium, but apparently not in the role of selenocysteine. See the review by T. Stadtman (23). Thomas H. Jukes
ACKNOWLEDGMENTS Many people have contributed to this brief biog raphy, and their affection and respect for the subject has been heartwarming. Among others, special thanks are due to members of Dr. Frost's family, Muriel (Mitzi) Frost and Melodie Cooey, and to the fol lowing: Manfred Anke; Jack Bauernfeind; Simon Black; Herbert Boynton,- Sam Carapella,- Charles Cooper; Mark Hegsted; Thomas Jukes,- Floyd Mclntyre; Charles Mellen,- Walter Mertz; Olaf Mickelsen,Bernard Schermetzler,- Irvin Smith; Louis Sokol; Chris Stater,- Sally Swift; Ernest Volwiler; Harold Zaugg and Ralph Zingaro.
LITERATURE CITED 1. Frost, D. V. &.Elvehjem, C. A. (1939)Factor W and its relation to the vitamin B complex. J. Biol. Chem. 128: 23-29. 2. Elvehjem, C. A., Madden, R., Strong, F. M. A. Woolley, D. W. (1937) Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J. Am. Chem. Soc. 59: 1767-1768. 3. Frost, D. V. (1967) Arsenicals in biology—retrospect and pros pect. Fed. Proc. 26: 194-208. 4. Frost, D. V. (1980)The two faces of arsenic—can arsenophobia be cured? In: Arsen 3. Spurunelement Symposium, pp. 17-23. Karl Marx University, Leipzig, Germany, and Friedrich Schiller University, Jena, Germany. 5. Kroes, R., VanLogten, M. J., Berkovens, J. M., de Vries, T. fil van Eoch, C. J. (1974) Study of the carcinogenicity of lead arsenale and sodium arsenale and the possible syncrgistic effect of dimethylnitrosarnine. Food Cosmet. Toxicol. 12: 671-679. 6. Jukes, T. H. &. Welch, A. D. (1942) The effects of certain analogs of choline on perosis. J. Biol. Chem. 146: 19-24. 7. Morehouse, N. F. & Mayfield, O. J. (1946) The effect of some aryl arsonic acids on coccidiosis infection in chickens. J. Parasitol. 32: 20-24. 8. Frost, D. V. (1960)Arsenic and selenium in relation to the food additive law of 1958. Nutr. Rev. 18: 129-132. 9. Shamberger, R. J. &. Frost, D. V. (1969) Possible protective effect of selenium against human cancer. Can. Med. Assoc. J. 100: 682-683. 10. Frost, D. V. (1972) Regarding the paper 'Essential trace metals: selenium' by Schroeder, H. A., D. V. Frost and J. J. Salassa (Letter to the Editor). J. Chronic Dis. 25: MS397. 11. Schwarz, K. &.Foltz, C. M. (1957) Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration. J. Am. Chem. Soc. 79: 3292-^2,93. 12. Patterson, E. L., Milstrey, R. & Stokstad, E.L.R. (1957)Effect of selenium in preventing exudative diathesis in chicks. Proc. Soc. Exp. Biol. Med. 95: 617-ÄW. 13. Eggert, R. O., Patterson, E., Akers, W. J. &. Stokstad, E.L.R. (1957)The role of vitamin E and selenium in the nutrition of the pig. J. Anim. Sci. 16: 1037-1042. 14. Muri, O. H., Oldfield, J. E., Remmert, L. R. &. Schubert, J. R. (1958) Effects of selenium and vitamin E on white muscle disease. Science (Washington, DC) 128: 1090. 15. Hartley, W. J., Grant, A. B. &. Drake, C. (1960) Control of
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
My findings [slight growth responses in rats to nicotinic acid, nicotinamide and adenine nucleotide, reported by Frost and Elvchjcm (2)],plus Knight's discovery of nicotinamide as a growth factor for Staph. auieus, plus knowledge of the great stability of nicotinic acid to acid and alkali made me certain that nicotinic acid should be tested in dogs. I had urged Bob Madden to boil up Carl Koehn's water white concentrate from liver that cured blacktongue, first with acid and next with alkali. Bob used my ground glass equipment for both and we had to break the one he used with NaOH to get the joints apart. He told me that both cured blacktongue after neutralization. In all fairness, Tom, Connie Elvehjem was not impressed and Madden fed nicotinic acid after my strong urging. Connie was very busy with more than 30 grad students and none of us had much time with him. The FrostElvehjem paper was received for publication 8/5/37 and the discovery letter by Elvehjem and co-workers (2) came more than a month later. In the Elvehjem, Madden, Strong, Woolley (20) paper, much of my literature review of the relation of nicotinamide to coenzyme and cozymase is used verbatim. I became convinced that my role had been too prominent and being offered the prime job as Connie's teaching assistant was automatically shifted to research with Hart and Elvehjem on the copper, iron research, which tradi tionally went with that job. I made it research with Cu, Fe and Co and just kept on working harder than ever. It so happened my folks invited me to help them drive to Yel lowstone in August, 1937. When we got back to Madison, Connie had already sent in his letter to the JACS and I was off the B-Complex research completely. I did more literature research tracing Casimir Funk's failure to place just where N.A. fit in the B-complex, but was soon far too busy with other research and teaching to do much else. I was extremely beholden to Connie for giving me the chance to serve as a grad student and realized how much the breakthrough would mean to him
DOUGLAS VAN ANDEN
16.
17.
19.
20.
21. 22.
23.
411
Zenobiotic Metabolism: Nutritional Effects. (Finley, J. W. & Schwärs,D. E., eds.) pp. 267-282. American Chemical Society Symposium Series 277, Washington, DC. Elvehjem, C. A., Madden, R. J., Strong, F. M. & Woolley, D. W. (1938) The isolation and identification of the anti-black tongue factor. J. Biol. Chem. 123: 137-149. Jukes, T. H. (1974) Dilworth Wayne Woolley. J. Nutr. 104: 509-511. Hiatt, H. H., Watson, J. D. &. Winsten, J. A (1977) Origins of Human Cancer. Book A, pp 2-4, 147-148. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Stadtman, T. (1990) Selenium biochemistry. Annu. Rev. Biochem. 59: 111-127.
Downloaded from https://academic.oup.com/jn/article-abstract/122/3/405/4754855 by Tulane University Medical Library user on 13 January 2019
18.
white muscle disease and ill-thrift with selenium. N. Z. J. Agrie. Res. 101: 343-347. Scott, M. L. & Thompson, J. N. (1968) Selenium in nutrition and metabolism, pp. 1-10. In: Proceedings of the Maryland Conference for Feed Manufacturers, College Park, MD. McCoy, K.E.M. &. Weswig, P. H. (1969) Some selenium responses in the rat not related to vitamin E. J. Nutr. 98: 383-389. Harr, J. R., Bone, J. F., Tinsley, I. J., Weswig, P. H. &. Yamamoto, R. W. (1967) Selenium toxicity in rats. H. Histopathology. In: Symposium: Selenium in Biomedicine, pp. 153-178. Avi Publishing, Westport, CT. Mimer, J. A. (1985) Selenium and carcinogenesis. In:
FROST
