The Two Faces of Selenium Deficiency and Toxicity Are Similar in Animals and Man

The Two Faces of Selenium Deficiency and Toxicity are Similar in Animals and Man

L.D. Koller and J.H. Exon*

ABSTRACT minimum daily requirement for immune system has a role in preven- optimum biological performance. tion of cancer, these data would The purpose of this review article is Recognizing that humans in several suggest that those neoplasms which to demonstrate the close parallelism of countries do not meet the proposed are natural killer cell-sensitive could daily requirements, biological activity minimum daily requirement of 90 ,ig, be prevented and/or respondent to and minimum and maximum tolera- several compelling reasons are pres- selenium therapy while those which ble levels of selenium for animals and ented in deriving this minimal daily are natural killer cell-insensitive could man. In addition, the carcinogenic/ nutritional intake. be augmented by selenium treatment. anticarcinogenic properties of sele- Selenosis can occur in laboratory Further investigations are warranted nium are discussed and a postulate of animals, livestock, and humans to dispute or confirm this hypothesis. how these dichotomous effects may following long-term exposure to The intriguing feature of selenium occur in accordance with selenium- selenium concentrations as low as 5 nutrition is the remarkable interspe- induced immunomodulation is pres- mg selenium/kg of diet (5 ppm). The cies similarities of the action of this ented. A review of pertinent literature selenium-induced lesions for all element, especially between animals pertaining to the biological action of species are similar, which once again and man. With few exceptions, direct selenium in animals and man, includ- illustrates a positive corollary for extrapolations between species have a ing deficiency, toxicity, carcinogenic- selenium effects in both animals and high degree of correlation. We believe ity and effects on immunity, is man. From compilation of available that many of the long-term myths included to support these concepts. data, the maximum tolerable level for concerning selenium have been dis- The predominant biochemical selenium in man could be considered pelled and anticipate that recognition action of selenium in both animals and in the range of 1000 to 1500 ,ig/day. of the biological importance, as well as man is to serve as an antioxidant via This is in contrast to the currently limitations, of selenium nutrition will the selenium-dependent enzyme, recommended maximum human tol- unequivocally benefit human and glutathione peroxidase, and thus erable level of 500 ,ug/day. The animal health. protect cellular membranes and amount of selenium that can be organelles from peroxidative damage. tolerated, however, is dependent upon Key words: Selenium, deficiency, The signs and symptoms of selenium individual biological variation, nutri- toxicity, carcinogenicity, immunity, deficiency closely simulate each other tional status and general state of animals, man. for animals and man. Severe defi- health. Therefore, individuals who ciency is characterized by cardiomy- consume relatively large daily opathy while moderate deficiency amounts of selenium should periodi- RESUME results in less severe, myodegenerative cally have their blood concentrations syndromes such as muscular weakness monitored and closely observed for Cet article comporte une revue de la and pain as well as a variety of other symptoms of toxicity. litterature pertinente et vise a selenium-associated diseases. Clinical Selenium, once labeled as a carcino- demontrer le parallelisme etroit qui manifestations of many of these gen, is now thought to possess existe entre les besoins quotidiens, disorders require contributory factors, antineoplastic properties. Studies in I'activite biologique, ainsi que les such as stress, to precipitate symptoms our laboratory, investigating the quantites tolerables minimales et which are documented for animals effects of excess selenium on immun- maximales de selenium, pour les and implicated for humans. Current ity, could possibly provide a plausible animaux et l'homme. Les auteurs evidence suggests that a daily selenium explanation for these contrasting commentent en plus les proprietes consumption for man of approxi- data. Rats given selenium supple- carcinogenes et anticarcinogenes du mately 30 ,ug is necessary to prevent mented diets had suppressed humoral selenium et presentent un postulat sur the selenium-deficient syndrome, and cell-mediated immune responses la facon dont ces effets dichotomes Keshan disease, while approximately but markedly stimulated natural killer peuvent survenir, en accord avec une 90 ,ug/day/adult should be the cell cytotoxicity. Assuming the immunomodulation provoquee par le

*Department of Veterinary Medicine, University of Idaho, Moscow, Idaho 83843. Present address of Dr. Koller: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331-4802. Submitted April 12, 1985.

Can J Vet Res 1986; 50: 297-306. 297 selenium. Ils ajoutent aussi, pour la quantite tolerable maximale de toxicite, effet carcinogene, immunite, supporter ces concepts, une revue de la selenium, chez l'homme, se situerait animaux, homme. litterature relative a l'action entre 1000 et 1500 ,g/jour. Une telle biologique du selenium, chez les conclusion contraste avec la recom- animaux et l'homme, y compris sa mandation courante de 50,tg/jour. La deficience, sa toxicite, ses proprietes quantite tolerable de selenium depend INTRODUCTION carcinogenes et ses effets sur toutefois des variations biologiques l'immunite. individuelles, de l'etat nutritionnel et Selenium (Se) has been recognized La principale action biochimique de l'etat general de la sante. Les for years as an essential trace element du selenium, tant chez les animaux individus qui consomment une quan- for animals (1), but until recently, it que chez l'homme, consiste 'a servir tite quotidienne relativement elevee de has not been recognized as an essential d'antioxydant, par le truchement de la selenium devraient donc en faire element for man. In the United States, glutathion-peroxydase, enzyme qui verifier periodiquement leur teneur the regions with the lowest amounts of depend du selenium, et a proteger ainsi sanguine et il faudrait les surveiller de Se in soils and plants are the les membranes et les organelles pres, afin de detecter les symptomes Northwest, Northeast, Southeast and cellulaires des dommages attribuables d'intoxication. areas of the Midwest which adjoin the au peroxyde. Les signes cliniques que On pense maintenant que le Great Lakes (2-4). The Plains States manifestent les animaux ressemblent selenium, deja identifie comme un and Southwest generally have ade- beaucoup aux symptomes qu'on agent carcinogene, possederait des quate Se in soils and plants. The observe chez l'homme, lors d'une proprietes antineoplasiques. Les majority of livestock raised in low Se deficience en selenium. Une deficience etudes relatives aux effets d'un exces regions generally do not receive marquee se caracterise par une de selenium sur l'immunite, realisees adequate dietary Se and thus are cardiomyopathie, tandis qu'une dans notre laboratoire, fourniraient deficient. Extreme Se deficiency in deficience moderee entraine des une explication plausible pour ces man has been more difficult to syndromes moins graves de donnees contradictoires-. Des rats demonstrate in the United States, degenerescence musculaire, tels que de auxquels on donnait des aliments primarily due to transportation of la faiblesse musculaire et de la enrichis de selenium manifesterent une consumable products from region to douleur, ainsi qu'une variete d'autres suppression de leur immunite humo- region. Nevertheless, Se deficiency in maladies reliees au selenium. Les rale et cellulaire, en meme temps man is well documented in China (5- manifestations cliniques de plusieurs qu'une stimulation marquee de la 10) while the extremely low Se content de ces conditions requierent des cytotoxicite naturelle de leurs phago- of New Zealand forages results in facteurs auxiliaires tels que le stress, cytes. Si on admet que le systeme relatively low Se concentrations in pour acceler l'apparition des immunitaire joue un role dans la both animal and human populations symptomes, qui sont documentes pour prevention du cancer, les constata- (1 1). les animaux et impliques chez tions precitees permettent de penser l'homme. L'evidence courante suggere qu'on pourrait prevenir les FUNCTION OF SELENIUM que les humains doivent consommer neoplasmes sensibles-aux phagocytes The biochemistry and mechanisms quotidiennement environ 30,ug de et/ou les amener "a repondre 'a une of action of Se have recently been selenium, pour prevenir la maladie de therapie a base de selenium, alors reviewed (12-14). Selenium is an Keshan, tandis que les adultes doivent qu'on pourrait stimuler les autres par important deterrent of lipid peroxida- en prendre au moins 90 ,ug/jour, pour cette therapie. II faudra realiser des tion, competes with sulfur in biochem- realiser une performance biologique experiences additionnelles, pour ical pathways, and is incorporated optimale. Tout en admettant que les infirmer ou confirmer cette hypothese. into the sulfur-containing amino habitants de plusieurs pays -fe con- Le point intriguant du metabolisme acids, cystine and methionine (15-17). somment pas cette dose quotidienne du selenium reside dans les ressem- Selenium is incorporated into minimale, on invoque plusieurs blances remarquables de son action enzymes which regulate normal body raisons valables pour la recom- chez les differentes especes, particu- processes. One Se-dependent enzyme mander. lierement chez lhomme et les ani- is glutathione peroxidase (GSH-Px) L'intoxication par le selenium peut maux. Sauf pour quelques exceptions, (13,17,18). Glutathione peroxidase se produire chez les animaux de les extrapolations directes entre les protects cellular membranes and lipid- laboratoire ou domestiques et chez les especes affichent une etroite correla- containing organelles from peroxida- humains, a la suite de -l'ingestion tion. Les auteurs croient que les vieux tive damage by inhibition and destruc- prolongee d'aussi peu que 5 mg de cet mythes relatifs au selenium ont ete tion of endogenous peroxides, acting element/kg d'aliments, i.e. 5 ppm. Les dissipes et ils anticipent que la in conjunction with vitamin E to lesions attribuables a cette intoxica- reconnaissance de son importance maintain integrity of these membranes tion se ressemblent, chez toutes les biologique et de ses limites contribu- (13,19). Glutathione peroxidase cata- especes; ce phenomene illustre une fois era sans equivoque a l'amelioration de lyzes the breakdown of hydrogen de plus un corollaire positif sur les la sante de l'homme et des animaux. peroxide (H202) and certain organic effets du selenium, tant chez les hydroperoxides produced by glutathi- animaux que chez l'homme. D'apres la one during the process of redox compilation des donnees disponibles, Mots cles: selenium, deficience, cycling (12,13). The toxicity of redox

298 cycling compounds is generally condition, "white muscle disease", is a encephalomalacia in chicks and increased by Se deficiency which myodegenerative disorder of calves nutritional dystrophy in rabbits and results in nearly a twofold increase in and lambs (16). Affected young guinea pigs, while Se prevents nutri- glutathione-S-transferase activity and animals may die suddenly due to tional muscular dystrophy in goats, glutathione synthesis in liver (20,21). myocardial dystrophy. This form lambs and calves, but not in rabbits or Five proteins other than GSH-Px occurs more often in lambs than guinea pigs. Therefore, even though that incorporate or require Se are the calves. The more common subacute Se and vitamin E complement each selenoprotein of muscle, selenoflagel- form is characterized by signs of other in many conditions, they cannot lin, Se-transport protein, and the stiffness, weakness and trembling of replace one another for prophylaxis in bacterial enzymes, formate dehy- the limbs frequently followed by the certain specific diseases. drogenase and glycin reductase inability to stand. The muscles may Stress may be an important factor (12,14). There is further evidence that tremor when the animal is forced to required to express many of the Se- Se is an essential component of stand. These muscles frequently feel associate diseases. For example, a nicotinic acid hydroxylase, xanthine hard and are swollen. Involvement of severe myopathy in Se-deficient dehydrogenase and a bacterial thio- the diaphragm and intercostal muscles yearling cattle can be precipitated by lase (12,14). Other selenoproteins and results in dyspnea and labored stress (exercise, transportation, etc.) selenoamino acid transfer nucleic breathing. The major clinical signs in (53-55). We have observed that acids have been identified but remain calves are primarily due to involve- combination of stress from cold and undefined (14). ment of skeletal muscles. Se deficiency produce weakness in Selenium facilitates significant Other diseases, probably of equal newborn calves. Further, since Se changes in metabolism of many drugs importance in cattle with Se defi- deficiency compromises the immune and xenobiotics. For instance, Se ciency, are weakness of neonatal system, it is possible that additional functions to counteract the toxicity of calves (30,3 1), calf scours and pneu- stress may render animals more several metals such as arsenic, cad- monia (32,33), unthriftiness and susceptible to infectious agents (See: mium, mercury, copper, silver and reduced weight gain (16,34-36), Selenium and Immunity Section). lead (22). On the other hand, some stillbirths and abortion (16,33,37), This may be a particularly important metals such as tellurium and zinc are retained placentas (38-40) and dimin- facet to recognize since most animals antagonists to Se and can interfere ished fertility (16). are only marginally deficient in Se and with the absorption or action of Se Many of the more subtle Se- clinical signs associated with Se- (23,27). Selenium has also been associated conditions in sheep are deficiency remain unrecognized. reported to alter cytochrome-P-450- similar to those observed in cattle. dependent drug metabolism (28). These include unthriftiness (16,35,36), DIAGNOSIS OF SELENIUM DEFICIENCY IN Excess Se also results in increased stillborn and weak lambs (32), ANIMALS synthesis of hepatic glucose-6- abortion (32), stifflambs (16), reduced Determination of the Se status of phosphate dehydrogenase, glutathi- fertility (16,41,42), multiple birth and livestock has become markedly one reductase and gamma-glutamyl- decreased wool production (32). improved during the past few years transpeptidase, thus shifting hepatic Several disorders in swine have been with the discovery that Se levels in glutathione toward a more oxidized associated with Se deficiency such as blood closely correlate with GSH-Px state (29). These data demonstrate the nutritional myopathy, mulberry heart activity (56-63). Selenium is an modifying effects of Se on the disease, hepatosis dietetica, gastric essential component of GSH-Px metabolism and toxicity of numerous ulcers, diarrhea and weakness of (17,18) and is incorporated into xenobiotics. piglets at birth (34,36,43-46). erythrocyte GSH-Px during erythro- Diseases associated with Se defi- poeisis (62). A direct relationship SELENIUM DEFICIENCY IN ANIMALS ciency in the horse are more ambigu- between blood Se concentrations and Selenium deficiency in livestock ous than in other livestock. Several blood GSH-Px activity occurs in provokes a myriad of diseases with a conditions in the equine respond to cattle, sheep, horses, chickens and potential to afflict enormous yearly Se-vitamin E therapy including rats. economic loss to producers. These various form of myopathies such as Since as much as 98% of GSH-Px diseases range from the well recog- myositis (tying-up) and polymyositis, activity in peripheral blood is asso- nized, ominous, severe condition of as well as azoturia (32,47,48). Other ciated with erythrocytes (60), analysis nutritional muscular dystrophy, conditions which may respond to Se- of red blood cells for GSH-Px activity "white muscle disease", to the numer- vitamin E therapy are infertility in is effective for determining the Se ous less explicit conditions often mares, muscular weakness in foals and status of animals. However, it must be referred to as Se-associated or Se- performance during exercise (racing, kept in mind that the activity of this responsive diseases. Some of the Se- etc.) (49,52). enzyme in erythrocytes will depend associated / responsive diseases are In poultry, exudative diathesis, upon availability of Se during erythro- characterized by muscular weakness encephalomalacia and muscular dys- cyte development (69). Therefore, of the newborn, unthriftiness, reduced trophy in chicks are associated more erythrocyte GSH-Px activity is a weight gain, diarrhea, stillbirths, with deficiencies of vitamin E than Se relatively stable biological indicator of abortions and diminished fertility. (19). It is interesting to note that Se while Se analysis of whole blood, The commonly known Se-deficient vitamin E is required for prevention of which contains both enzymatic and

299 nonenzymatic components, is affected Se was provided in drinking water, considered an essential trace element by daily variations in Se intake. weight gain was equivalent for treated for human nutrition (7,11). Selenium Blood Se levels less than 0.05 ,ug/ and nontreated controls (73). Pro- deficiency has clearly been associated mL (ppm) are considered as Se longed exposure of rats to elevated with health problems in animals, but deficient while levels between 0.05 and levels of Se resulted in mottling and only recently have Se deficient 0.10 are marginal, and greater than discoloration of the liver, hyperplasia disorders in man been unequivocally 0.10 are adequate (63). Comparable and hepatic cirrhosis (71). defined. The most prominent of these whole blood GSH-Px levels are: Livestock exhibit several manifesta- conditions, known as Keshan disease, deficient if less than 30 mU/mg tions of selenosis. A single dose of 2 is endemic in certain regions of China. hemoglobin; marginal if 30-60 mU/ mg Se/kg body weight administered Keshan disease is a cardiomyopa- mg; and adquate if greater than 60 to neonatal calves resulted in lassi- thic condition characterized by heart mU!/mg hemoglobin (63,64). tude, inappetance, dyspnea and death failure, cardiac enlargement, abnor- within 12 hours following injection malities of ECG, gallop rhythm and SELENIUM TOXICITY IN ANIMALS (74). Others have reported the min- even cardiac shock. This disease is Selenium toxicity in laboratory imum lethal dose of a single injection reported to occur predominately in animals and livestock has been fairly of Se to be much greater for cattle. An children and women of child-bearing well characterized in numerous oral dose of 20 mg Se/ kg body weight ages (5-10). In the early 1970s, the reviews and texts and will only be (sodium selenite) proved fatal to a calf condition was found to be prevented discussed briefly herein. There appear in six hours (75), while in another by Se therapy and the high morbidity to be only minor variations in study, 9.9 to 11 mg Se/ kg body weight of nearly 50% was essentially elimi- susceptibility to acute toxicity was determined to be the minimal nated (7,10). Mortality was not between species. Selenite and selenate lethal dose (76). In another study (77), uncommon in severely afflicted produce similar acute toxic effects. 2 mg Se/ kg body weight produced individuals. This was the first human The minimum lethal dose of selenite or 100% mortality in swine within four disease directly linked to Se deficiency selenate in rabbits, rats, dogs and cats hours of injection. A lower dose of 1.2 and provoked the suggestion that Se was 1.5 to 3.0 mg/kg body weight mg Se/ kg body weight produced 100% be classified as an essential trace regardless of route of administration mortality in five days. The FDA has element for man (5,6,1 1). (65,66). Signs of acute poisoning are approved Se as a feed additive for The Se content of soil and foliage in garlicky breath, vomiting, dyspnea, cattle, sheep, swine and chickens and New Zealand is extremely low and Se- tetanic spasms and death from permits a level of 0.1 ppm Se of the deficient diseases are prevalent in respiratory failure (67). Histopatho- total diet (78-80). The maximum untreated livestock. Human blood Se logical lesions include congestion of dietary tolerable levels of Se for levels are also low but Se-deficient the liver and kidneys, focal necrotic livestock has been set at 2 ppm (1). syndromes are not expressed unless hepatitis, endocarditis, myocarditis "Blind staggers" is a clinical accompanied by contributing factors and petechial hemorrhages of the expression for subacute selenosis in such as stress. For example, a Se- epicardium (68). livestock. Affected animals exhibit responsive muscular syndrome was Chronic toxicity studies have impaired vision, abdominal pain, described in a surgical patient on total indicated that diets containing 5 mg/ anorexia, ataxia, paralysis and death. parenteral nutrition (1 1). Individuals kg or more of Se result in chronic Chronic exposure to Se results in a with a variety of debilitating disorders toxicity in laboratory animals (68-73). condition in livestock known as also exhibited symptoms of Se- The National Academy of Sciences "alkali disease". This disorder is deficiency. In our studies as well as has accepted 5 mg Se/kg diet as the characterized by lack of vitality, others with livestock (53-55, 82,83), we division level between toxic and anemia, stiffness of joints, deformed have observed that a variety of stresses nontoxic feeds (69). and sloughed hoofs, roughened hair may indeed precipitate expression of Sodium selenite or naturally occur- coat and lameness. Se-deficient syndromes. Others have ring Se fed in diets of rats at 1.6, 3.2 In general, the minimal acute lethal reported deficient syndromes in and 4.8 ppm for six weeks had no dose of Se for livestock ranges from 1- humans who received total parenteral significant effect on growth (72). 5 mg/ kg body weight. A diet contain- nutrition (84,85). The symptoms Impaired growth and increased spleen ing 5 ppm Se for an extended period included intermittent muscle tender- weights occurred in rats fed 6.4 ppm may produce signs of toxicosis while a ness and pain and eventual white Se. Concentrations of 8.0 mg Se/kg more severe form of selenosis will fingernail beds. In addition, the feed resulted in increased mortality occur at 10-25 ppm Se (81). The activity of glutamic oxaloacetic rates, enlargement of the spleen and recommendation of the National transaminase, glutamic pyruvic tran- pancreas, reduced liver-to-body Academy of Science that diets con- saminase and creatine kinase in serum weight ratios and decreased blood taining 5 ppm of Se or more may result was elevated. hemoglobin. in chronic toxicity in laboratory Epidemiological studies suggest In a two year study, rats fed 0.5 ppm animals could also pertain to live- that Se deficiency may contribute to Se were comparable to controls while stock. cardiovascular disease of man (86-88). levels of 4 ppm impaired growth and The incidence of hypertensive heart reduced survivability (71). However, SELENIUM DEFICIENCY IN HUMANS disease is significantly lower in Se in another two year study when 4 ppm It was recently suggested that Se be adequate areas of the U.S. compared

300 to Se deficient areas (89). Likewise, in Prolonged intravenous treatment of a disease. The maximum amount con- Finland, high mortality from heart patient deficient in Se with 42 mg/day sumed by individuals in this group disease occurs in areas low in Se (86). elemental Se (H2SeO3) markedly without symptoms was 1510 Mg/day. The amount of blood Se in Keshan improved both blood Se and whole Mean blood Se levels for the five disease patients was in the range of blood GSH-Px activity (84). Thus, Se different groups were reported as high 0.020 to 0.026,g/ mL (7,10). Selenium therapy is effective in both prevention Se with selenosis - 3.2,Mg/ mL; high Se levels in the hair of afflicted individu- and treatment of Se deficient syn- without selenosis - 0.44 Mug/ mL; Se- als ranged from 0.07 to 0.12 ,g/g dromes in man. adequate - 0.095 Mg! mL; low Se - (7,10). Individuals in low Se areas 0.027 Mg! mL; and low Se with Keshan without symptoms of Keshan disease SELENIUM TOXICITY IN HUMANS disease - 0.021 ,ug/mL. The average had mean blood Se levels of 0.027 ,ug/ The enigma surrounding toxicity of blood concentration of Se in the high mL and Se of 0.16,utg/g in hair (10). A Se in man has for decades created Se with selenosis group was about 30 human population considered to be considerable debate. Nutritionists and times that of the Se-adequate group Se-adequate had mean blood and hair regulatory agencies have been per- and 160 times that of the Keshan Se concentrations of 0.095 and 0.36 plexed in attempts to derive the no- disease patients. The highest blood Se MAg/g, respectively (10). It has been observable-adverse-effect, lowest- values, 7.5 Mg/mL, in one individual proposed that a minimum adequate observable-adverse-effect, or min- exceeds the critical level most experi- whole blood Se level to prevent imum toxic effect levels for humans. mental animals can tolerate and was Keshan disease is in the range of 0.03- Establishment of upper limits of Se nearly 350 times higher than the 0.04 ,Ig/ mL with corresponding levels exposure for man was based either average value (0.021 MAg! mL) for of Se in hair of greater than 0.2 ,Lg/g solely on animal data or a scattering of Keshan disease patients. (7). The estimated minimum daily Se epidemiological studies in absence of Both hair and blood Se concentra- requirement to prevent Keshan dis- appropriate experimental or quantifi- tions were reliable criteria for Se ease would be approximately 30 ,ug able epidemiological data by which to exposure, while urinary Se was (7,10). The average daily Se intake make sound judgments. Thus, in order variable and considered unreliable even in low Se areas was approxi- to protect human populations from (10). The ratio of maximum tolerable mately three times that of the Keshan excessive consumption of Se, 500 Mg level vs minimum levels to protect disease patients (10). This suggests of Se was generally accepted as the against Keshan disease for hair and that the minimum daily requirement maximum acceptable daily intake. blood were 26 and 16, respectively. for Se for an adult would be a However, recent information would However, the mean daily Se intake of minimum of 90 ,ug. These values suggest this level is unreasonably low adults in the high Se areas without approximate the minimum daily and should be increased at least one to selenosis (750 Mug) was about 70 times requirement recommended for anim- twofold. that for the Keshan disease group. als. Although the average daily intake A report in 1978 suggested that In a separate case report described of Se in some countries does not meet humans could consume 600 Mg Se per within this article (10), a 62 year old the 90 Mg level (11), lesser amounts day for 18 months without any adverse man consumed 1 mg elemental Se as may be sufficient for Se-dependent health effects (90). The blood Se sodium selenite per day for two years body functions in the absence of concentration at this level of exposure until development of mild signs of contributing factors such as stress. was 0.62 ug/mL. A recent epidemio- intoxication. The concentrations of Se Further, vitamin E and other nutri- logical study objectively quantifies the in his blood and hair were 0.179 MAg! tional factors may be compensatory in range of Se consumption, accompan- mL and 0.828 Mug/g, respectively, on regard to expression of severe Se- ied by blood and hair concentrations, the day intake was discontinued. deficient syndromes in man. which provides useful data to predict Symptoms of Se toxicosis for man Treatment of Se deficiency has been minimum and maximum levels which are a garlic odor of the breath, successful in humans (5,7,84,85). An would result in adverse health effects thickened and brittle fingernails with incidence rate of 9.5-13.5/ 1000 of in man, i.e. deficiency or toxicity (10). white spots or longitudinal streaks, Keshan disease in endemic areas was The report documents five levels of hair that is dry, brittle and easily reduced to 1-2/ 1000 in children long-term Se consumption in man, i.e. broken off at the scalp, red, swollen treated once a week with 0.5-1 mg high Se with chronic selenosis, high Se skin of hands and feet that may blister sodium selenite (7). In another study, in the absence of selenosis, Se or even ulcerate, excessive tooth decay intravenous infusion of 100 ug adequate, low Se and low Se resulting and abnormalities of the nervous selenomethionine alleviated symp- in Keshan disease. The daily dietary system inclusive of numbness, convul- toms of selenium deficiency but was intake of Se averaged 4.99 mg/day sions and paralysis. Symptoms accompanied by only a small increase (range 3.20-6.69) for the group with depend on severity of toxicosis. in plasma and whole blood Se (85). chronic selenosis. Symptoms of In summary, endemic selenosis in This suggests a critical point in toxicity which developed in this group man has occurred in areas where the supplementation before Se residues in rescinded when their diets were average daily Se intake was 4.99 mg, blood become elevated and return to replaced with foods which contained while another group which received a normal ranges. Similar results have nontoxic amounts of Se. Individuals mean daily intake of 0.75 mg (high of been reported for Se deficient beef receiving an average daily intake of 1.51 mg/day) did not develop seleno- cattle supplemented with Se (64). 750 MAg Se did not exhibit signs of sis. An individual consuming 1 mg of

301 Se daily for two years, in addition to a tion of tumor genesis. The effect of Se burst of phagocytes (1 18). Accumula- normal dietary intake, developed only on immune function may further tion of H202 and other peroxides or mild signs of toxicosis. Therefore, complicate the issue of Se carcinoge- oxygen radicals can result in self- based on this information, it can be nicity/ anticarcinogenicity and will be destruction of a cell and have been predicted that chronic selenosis occurs discussed in the following section of implicated as nongenotoxic mediators in man with a daily intake of this article. of neoplasia. approximately 1000 to 1500 ,ug of There is no evidence that Se is Neutrophils, peritoneal macro- elemental Se. carcinogenic in humans. In fact, phages and pulmonary alveolar epidemiological data would suggest macrophages from Se-deficient anim- CARCINOGENIC PROPERTIES OF SELENIUM that Se may indeed protect against als have low amounts of GSH-Px Selenium was considered to be a human cancer. An increased incidence activity and decreased microcidal carcinogen for several years (70) and of colorectal, breast and other cancers activity (1 19-124). Further, the phago- this notion- impeded approval of Se as in humans occurred in geographic cytic capability of neutrophils was not a feed supplement for livestock. regions deficient in Se (108,109). diminished, but the ability of these Selenium was also unrecognized as an Further, the blood Se levels in humans cells to destroy the phagocytized essential trace element for humans who developed cancer during a five bacteria was compromised (121,124). until recently and, consequently, year period were significantly lower Evidence has been presented that Se- interest in Se as a human nutrient than were those for matched control deficient neutrophils have decreased waned. Nevertheless, this element was subjects (110). Low Se levels were superoxide dismutase-sensitive reduc- eventually recognized for its impor- associated primarily with cancer on tion of both cytochrome C and 2-(p- tance of maintaining health of lives- the gastrointestinal tract and prostate. iod ophenol)-3-(p-nitrophenyl)-5- tock, and research progressed slowly Thus, recent information would dispel phenyl tetrazolium chloride (INT) for the next couple of decades. The that Se is a carcinogen and actually and, thus, diminished ability to advancement of technology and newly suggest that Se is a potential and produce superoxide radials (0-O) acquired knowledge of the multistep perhaps formidable anticarcinogen. required for microbial activity. In fact, process of neoplasia in the early 1970s Controlled investigations, particularly it has been proposed that peroxide- resulted in renewed interest in the those relevant to man, are warranted mediated cell injury could also carcinogenic action of Se. In fact, to validate and characterize the account for the reduction in lympho- several studies indicated that Se may antineoplastic properties of Se. cyte mitogenesis and enhancement of indeed be an anticarcinogen. A recent adjuvant arthritis in animals (1 17). A review (91) discusses the interactions dearth of information is available for of Se with a variety of carcinogens and SELENIUM AND IMMUNITY Se-associated immune function in illustrates the anticarcinogenic activ- The functioning immune system humans. However, one study indi- ity of Se. We will not attempt to requires adequate levels of Se for cated that granulocytes from Se- provide a complete review of the optimum performance. Selenium deficient individuals had a lower literature herein, but rather will briefly augments immunity and has a role in cytocidal capacity than did granulo- define some of the more pertinent inflammation. Animals deficient in Se cytes from Se-supplemented individu- recent reports which describe the and vitamin E had lower antibody als (125). Other immune parameters anticarcinogen properties of Se. titers in response to vaccination than examined were unaffected. Recently, Se supplementation was did nondeficient animals ( 1 1). Excess In our laboratory, we have observed shown to significantly inhibit both Se potentiated the protective effect of that excess dietary Se will significantly chemical- and virus-induced neoplasia a killed vaccine (112). Selenium has (P < 0.05) stimulate natural killer cell (92-101). The development of preneo- been reported to enhance antibody (NKC) cytotoxicity and concurrently plastic lesions was shown to be very synthesis, thereby amplifying the suppress both cell-mediated and sensitive to Se-mediated inhibition immune system in response to anti- humoral immune responses in rats (98). It has been postulated that Se genic stimulation (1 12-116). Selenium (126). The delayed-type hypersensitiv- inhibits the promotion phases of deficiency impaired mitogenic stimu- ity response was suppressed in rats fed carcinogenesis (107). Upon withdra- lation of lymphocytes in both dogs 0.5, 2.0 or 5.0 ppm Se for ten weeks wal of the Se supplementation, tumors (111) and mice ( 117). These data are while the humoral immune response will emerge at the same rate as those in indicative of the sensitivity of the was only impaired at the highest dose Se-untreated animals (97,99,102-104). humoral immune system to the (5.0 ppm). The high dose would be It has been suggested that Se presence of Se for normal function. considered near toxic levels in the rat protects against oncogenesis by Very little information is available to under prolonged exposure. Conver- inhibiting metabolic activation of indicate the influence of Se on cell- sely, the NKC activity was enhanced at carcinogens (105,106) but this mecha- mediated immunity in animals. 0.5 and 2.0 ppm with no effect nism remains unconfirmed (92). As mentioned previously, Se is a occurring at the 5.0 ppm Se level. The Another study (107) concluded that Se component of the active site of the effect of Se treatment on prostaglan- can inhibit both the initiation and enzyme, GSH-Px. A substrate for this din E2 (PGE2) and interleukin 1 promotion phases of carcinogenesis enzyme is hydrogen peroxide (H202) activity of macrophages was also and that a continuous intake of Se is which is generated during the oxida- assessed. Prostaglandin E2 activity necessary to achieve maximum inhibition processes, including the oxidative was significantly reduced at the

302 highest dosage of Se while interleukin metabolism of many drugs and daily requirement, a lesser amount 1 production was unaffected. xenobiotics. may be insufficient for optimum Immune surveillance of neoplasia Severe Se deficient syndromes are function of certain biological systems requires a variety of cells often expressed similarly in animals and when provoked by contributory working together in an interrelated humans. An example is the factors such as stress. This does indeed network which are intricately regu- cardiomyopathy-associated condition occur in animals and has been lated by numerous immunocytokines. in young livestock described as "white documented for man. Third, the Different types of cancer may be muscle disease". A comparable syn- overall nutritional status of a given sensitive to a particular immunocyte drome in humans is Keshan disease. demographic population may either population(s) such as cytotoxic T The cardiomyopathy occurs predomi- predispose, or conversely, partially cells, while others may be controlled nantly in children and mimicks both compensate for low Se intake. For more by macrophages or NKC. the lesions and age of the disease in instance, an individual low in vitamin Recent information favors the NKC as livestock. E may require more Se than an the primary effector of immune A counterpart of Se-associated individual with high levels of vitamin surveillance, keeping in mind that not diseases in animals occur in man, E. This is exemplified by what appears all tumor cells are NKC sensitive. particularly following stressful situa- to be a species specific, myodegenera- Nevertheless, the NKC serves as a tions such as surgery or in association tive, Se-deficient-like syndrome which model system to assess the develop- with debilitating diseases. For occurs in sheep deficient in vitamin E, ment, progression, regression as well instance, a Se-responsive muscular but possess adequate levels of Se (127). as prognosis for many types of tumors. syndrome has been described in Fourth, there is compelling evidence It can be postulated from immune surgical patients (11). These data in both laboratory animals and studies recently completed in our would suggest that the stress of livestock that marginal levels of Se laboratory (126) that perhaps the surgery in Se-marginal humans may may impair optimum function of marked enhancement of NKC activity precipitate syndromes similar to those complex biological systems such as the could be considered a mechanism reported for Se-marginal animals. endocrine and immune systems. underlying the anticarcinogenic prop- Diets which contain less than 0.1 Further knowledge must be acquired erties of Se. Thus, neoplasms that are ppm Se (100 ,ug Se/kg feed) are to better delineate these relationships. NKC sensitive could be prevented considered as inadequate and deficient Finally, the narrow margin between and/or respondent to Se therapy. On for livestock. Blood Se concentrations minimal daily requirement and maxi- the other hand, those neoplasms that of less than 0.05 ug! mL are regarded mum tolerable levels has been a are not NKC sensitive could actually as Se-deficient in animals, while levels deterrent for physicians to recom- be augmented since excess Se between 0.051 to 0.075 are low mend Se treatment. Expansion of this impaired both humoral and cellular marginal, 0.076-0.10 marginal, and margin as proposed herein would immunity. This hypothesis remains to greater than 0.10 adequate. Glutathi- reduce the concern of toxicosis due to be tested. one peroxidase provides a positive prescribed supplementation. correlation to Se for diagnostic It would appear from data accumu- SELENIUM-ASSOCIATED SIMILARITIES OF purposes (63). The values representa- lated from human studies and consid- ANIMALS AND MAN tive of Se status in humans are less ering the factors discussed above that A comparison of Se requirements of clearly demarcated, probably due in blood Se concentrations of less than animals and man is not available in the part to a more varied source of Se in 0.03 Mg/ mL represent severe defi- literature. The intention of this section the diet. However, the evidence ciency, 0.03-0.04 M!g/mL low margi- is to demonstrate the parallelism discussed previously strongly suggests nal, 0.04-0.075 M!g/mL marginal and which occurs in regard to Se function, that a daily Se requirement of greater than 0.075 M!g/mL adequate. deficiency, toxicity, lesions and other approximately 30 ,ug Se is necessary to These levels are slightly lower than factors in man versus animals. The prevent the Se-deficient syndrome, those designated for equivalent data from which this information was Keshan disease, in man and that at categories for livestock. extracted will, with an occasional least 90 M!g/day is the minimum daily Chronic Se toxicity will occur in exception, demonstrate that data requirement. The recommended min- laboratory animals and livestock fed derived from animal studies can be imum daily requirement of Se may be diets containing 5 mg/ kg of Se. A directly extrapolated to humans with greater than that previously proposed similar exposure to Se (4.99 mg/kg) predictable precision. for several reasons. First, the data resulted in chronic selenosis in man The pharmacokinetics and bio- collected from human studies in China (10). The lesions of selenosis for both chemical actions of Se are comparable ranging from severe Se deficiency to animals and man are similar as for man and animals. The predomi- toxicity, indicated that the average Se characterized by abnormalities of the nant function of Se as an antioxidant content of cereals grown in low Se hooves/nails, hair and skin, as well as is mediated through the action of the areas was approximately two to three the central nervous system. Se-dependent enzyme, GSH-Px, times that in areas where Keshan The information available on which which activates several biological disease patients resided (10). Second, to base a recommended maximum processes such as superoxide dismu- although the average daily intake of Se tolerable daily consumption of Se for tase. Selenium also synergizes the by humans in some countries is less humans is sparse but compelling. A action of vitamin E and facilitates than the 90 ,g proposed as a minimum lower limit, dependent upon individ-

303 ual biological variation and total case of cardiomyopathy and selenium and vanadium. Am J Vet Res 1981; 42: nutritional status, as well as other deficiency. New Engl J Med 1981; 304: 789-799. factors can be established. The group 1210-1211. 28. SHULL LR, BUCKMASTER GW, 10. YANG G, WANG S, ZHOU R, SUN S. CHEEKE PR. Effect of dietary selenium of individuals in China (10) classified Endemic selenium intoxication of humans status on in vitro hepatic mixed-function as high in Se, but without clinical signs in China. Am J Clin Nutr 1983; 37: 872- oxidase enzymes of rats. J Environ Pathol of toxicosis, had a mean daily intake 881. Toxicol 1979; 2: 1127-1138. of 750 ,ug Se with a maximum of 1510 11. THOMSON CD, ROBINSON MF. 29. LEBOEUF RA, HOEKSTRA WG. changes in hepatic glutathione same Selenium in human health and disease Adaptive g!g/day. In the study, long-term with emphasis on those aspects peculiar to metabolism in response to excess selenium daily consumption of 3.2 to 6.69 mg Se New Zealand. Am J Clin Nutr 1980; 33: in rats. J Nutr 1983; 113: 845-854. resulted in selenosis. In another 303-323. 30. MACE DL, TUCKER JA, BILLS CB, report, a man who consumed a daily 12. REDDY CC, MASSARO EJ. Biochemis- FERREIRA CS. Reduction in incidence supplement of 1 mg Se for two years, try of selenium: a brief review. Fund Appl of birth of premature, weak, or dead calves Toxicol 1983; 3: 431-436. following sodium selenite d-alpha toco- in addition to normal dietary Se, 13. BURK RF, LANE JM. Modification of pherol therapy in pregnant cows. Calif eventually developed minor symp- chemical toxicity by selenium deficiency. Dept Ag Bull 1963; No. 152: 21-28. toms of toxicosis which were reversi- Fund Appl Toxicol 1983; 3: 218-221. 31. HASTINGS DH. Selenium deficiency ble. These data taken together would 14. STADTMAN TC. New biologic functions associated with energy conversion facili- tolerable - selenium-dependent nucleic acids and ties. J Am Vet Med Assoc 1977; 171: 648. suggest that the maximum proteins. Fund Appl Toxicol 1983; 3: 420- 32. HERRICK JB. Abstracts on selenium- level for Se in man should be from 423. tocopherol. Ames, Iowa: Iowa State 1000 to 1500 ,g/day. Once again, 15. BURK RF. Selenium in nutrition. World University, 1979. individual biological variation and Rev Nutr Diet 1978; 30: 88-106. 33. REYNOLDS GE, OLDFIELD JE. White total nutrition as well as other factors 16. UNDERWOOD BJ, ed. Trace elements in muscle and other selenium-responsive human and animal nutrition. Chapter 4. diseases of livestock. A Pacific Northwest would predicate the actual amount of New York: Academic Press, 1977: 302- Extension Publication No. 157, Oregon Se resulting in toxicosis following 346. State University, 1976. prolonged exposure. Nevertheless, 17. FLOHE L, GUNZLER WA, SCHOCK 34. 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